The invention relates to cathepsin K polypeptides, polynucleotides encoding the polypeptides, methods for producing the polypeptides, in particular by expressing the polynucleotides, and agonists and antagonists of the polypeptides. The invention further relates to methods for utilizing such polynucleotides, polypeptides, agonists and antagonists for applications, which relate, in part, to research, diagnostic and clinical arts.

Bone resorption involves the simultaneous removal of both the mineral and the organic constituents of the extracellular matrix. This occurs mainly in an acidic phagolysosome-like extracellular compartment covered by the ruffled border of osteoclasts. Barron, et al., J. Cell Biol., 101:2210-22, (1985). Osteoclasts are multinucleate giant cells that play key roles in bone resorption. Attached to the bone surface, osteoclasts produce an acidic microenvironment between osteoclasts and bone matrix. In this acidic microenvironment, bone minerals and organic components are solubilized. Organic components, mainly type-I collagen, are thought to be solubilized by protease digestion. There is evidence that cysteine proteinases may play an important role in the degradation of organic components of bone. Among cysteine proteinases, cathepsins B, L, H, and S can degrade type-I collagen in the acidic condition. Etherington, D. J. Biochem. J., 127, 685-692 (1972). Cathepsin L is the most active of the lysosomal cysteine proteases with regard to its ability to hydrolyze azocasein, elastin, and collagen.
Cathepsins are proteases that function in the normal physiological as well as pathological degradation of connective tissue. Cathepsins play a major role in intracellular protein degradation and turnover, bone remodeling, and prohormone activation. Marx, J. L., Science. 235:285-286 (1987). Cathepsin B, H, L and S are ubiquitously expressed lysosomal cysteine proteinases that belong to the papain superfamily. They are found at constitutive levels in many tissues in the human including kidney, liver, lung and spleen. Some pathological roles of cathepsins include an involvement in glomerulonephritis, arthritis, and cancer metastasis. Sloan, B. F., and Honn, K. V., Cancer Metastasis Rev., 3:249-263 (1984). Greatly elevated levels of cathepsin L and B mRNA and protein are seen in tumor cells. Cathepsin L mRNA is also induced in fibroblasts treated with tumor promoting agents and growth factors. Kane, S. E. and Gottesman, M. M. Cancer Biology, 1:127-136 (1990).
The gene expression and cellular content of a non-cysteine protease, cathepsin D, in Alzheimer's disease brain showed evidence for early up-regulation of the endosomallysosomal system. Cataldo A. M., et al., Neuron, 1995, 14 (3), 671-680).
In vitro studies on bone resorption have shown that cathepsins L and B may be involved in the remodelling of this tissue. These lysosomal cysteine proteases digest extracellular matrix proteins such as elastin, laminin, and type I collagen under acidic conditions. Osteoclast cells require this activity to degrade the organic matrix prior to bone regeneration accomplished by osteoblasts. Several natural and synthetic inhibitors of cysteine proteinases have been effective in inhibiting the degradation of this matrix.
The isolation of cathepsins and their role in bone resorption has been the subject of an intensive study. OC-2 has recently been isolated from pure osteoclasts from rabbit bones. The OC-2 was found to encode a possible cysteine proteinase structurally related to cathepsins L and S. Tezuka, K., et al., J. Biol. Chem., 269:1106-1109, (1994).
An inhibitor of cysteine proteinases and collagenase, Z-Phe-Ala-CHN.sub.2 has been studied for its effect on the resorptive activity of isolated osteoclasts and has been found to inhibit resorption pits in dentine. Delaisse, J. M. et al., Bone, 8:305-313 (1987). Also, the effect of human recombinant cystatin C, a cysteine proteinase inhibitor, on bone resorption in vitro has been evaluated, and has been shown to significantly inhibit bone resorption which has been stimulated by parathyroid hormone. Lerner, U. H. and Grubb Anders, Journal of Bone and Mineral Research, 7:433-439, (1989). Further, a cDNA clone encoding the human cysteine protease cathepsin L has been recombinantly manufactured and expressed at high levels in E. coli in a T7 expression system. Recombinant human procathepsin L was successfully expressed at high levels and purified as both procathepsin L and active processed cathepsin L forms. Information about the possible function of the propeptide in cathepsin L folding and/or processing and about the necessity for the light chain of the enzyme for protease activity was obtained by expressing and purifying mutant enzymes carrying structural alterations in these regions. Smith, S. M. and Gottesman, M. M., J. Bio Chem., 264:20487-20495, (1989). There has also been reported the expression of a functional human cathepsin S in Saccharomyces cerevisiae and the characterization of the recombinant enzyme. Bromme, D. et al., J. Biol. Chem., 268:4832-4838 (1993).


When multiple communication terminals access a base station in CDMA in which transmission signals are spread with orthogonal codes, the orthogonal codes in CDMA signals transmitted from the communication terminals are synchronized on the communication path. The communication terminals each include an information acquirer acquiring reference time information common to the multiple communication terminals, a transmission time generator generating a chip clock on the basis of the time information, an orthogonal code generator generating orthogonal codes in time with the timing of the chip clock, a CDMA spreader spreading transmission signals with the orthogonal codes to generate code division multiple access signals, a carrier wave generator generating a carrier wave, and a BPSK modulator modulating the carrier wave generated by the carrier wave generator with the code division multiple access signals and transmitting the carrier wave.

Satellite communication access systems in which multiple terminal devices transmit to a base station via a nongeostationary satellite such as a quasi-zenith satellite in code division multiple access (CDMA) are known. On the other hand, techniques using orthogonal codes as a spread code sequence for CDMA communication are known.
For example, Non Patent Literature 1 describes an orthogonal Gold code sequence as a spread code sequence for code division multiple access (CDMA) communication. The Non Patent Literature 1 states that the generated orthogonal Gold code sequences are orthogonal to each other with a shift of 0.
Patent Literature 1 discloses a satellite communication system conducting data communication between a terminal device and a base station via an artificial satellite. The satellite communication system of the Patent Literature 1 generates transmission synchronization signals dividing reference synchronization signals obtained using the global positioning system (GPS) and synchronized with the current time into multiple time divisions, and spread code generation signals dividing the transmission synchronization signals into multiple time divisions. Upon transmission of data, a random number is generated and the data transmission starts when the number of transmission synchronization signals following reference synchronization signals becomes equal to the value of the random number. Furthermore, using spread codes sequentially output in sync with spread code generation signals, the modulated wave based on the transmission data is spread in spectrum to generate transmission signals.
In the random access control method disclosed in Patent Literature 2, the base station notifies the terminal devices of given delay time information. The terminal devices spread their transmission data with the same spread code, and set and transmit the spread transmission data of which the delay time is individually adjusted based on the notified delay time information in a specified slot.
Furthermore, Patent Literature 3 discloses a technique used in bidirectional satellite communication between a parent station and a mobile unit via a nongeostationary satellite such as a quasi-zenith satellite for frequency-compensating the carrier wave Doppler frequency shift caused by movement of the nongeostationary satellite based on orbit information of the nongeostationary satellite and location information of the mobile unit.
Non Patent Literature 2 discloses a basic study on bidirectional communication systems using a nongeostationary satellite. The Non Patent Literature 2 refers to prospects of using a quasi-zenith satellite or GPS satellite and transmitting very short messages such as someone's safety information via the satellite (quasi-zenith satellite). The Non Patent Literature 2 also discloses compensation of the carrier wave frequency deviation using GPS signals and compensation of the transmission delay difference using GPS signals.

Communication system, communication terminal, communication method, chip clock generation method, and orthogonal code generation method


A multilayer through-air dryer (TAD) fabric architecture having a single warp yarn system with a maximum warp fill and a weft yarn system comprised of two sets of weft yarns selected to set the warp yarn height above the weft yarns without embedment into the fabric plane, the warp and weft yarns interlacing to form diagonal apertures within the fabric to produce a high fabric air permeability for providing increased paper sheet bulk without compromising paper machine running parameters. A method of using the TAD fabric of the present invention for forming a paper sheet having increased bulk and a predetermined embossed pattern. Also, a method for manufacturing a TAD fabric to provide increased bulk and a predetermined embossed pattern of the paper sheet.

(1) Field of the Invention
The present invention relates generally to industrial textiles and, more particularly, to a multilayer papermakers fabric for use on through-air dryer sections of paper making machines.
(2) Description of the Prior Art
Typically, through-air drying machines employ paper machine clothing having weave designs and properties for assisting the transportation and drying of the paper sheet through that section of the machine. A through-air dryer (TAD) is a honeycomb or generally porous large diameter suction roll that follows the press section of a paper machine. It is at least partially surrounded by a hood that blows hot air. The paper sheet is carried on the TAD fabric over the periphery of the TAD cylinder; hot air from the hood impinges onto the paper sheet, passes through the sheet and the TAD fabric supporting the sheet into the porous suction roll.
Prior art TAD fabrics commonly employ single layer fabric designs, although double layer fabrics have also been known to be used. By way of example, the following prior art references are considered relevant to this application:
U.S. Pat. Nos. 5,672,248, 5,746,887, and 6,017,417, issued Sep. 30, 1997, May 5, 1998, and Jan. 25, 2000, respectively, to Wendt, et al. for Method of making soft tissue products teaches tissue products with increased cross-machine direction stretch and method for producing same. This property is imparted to the tissue by making the tissue using a throughdrying fabric having from 5 to about 300 machine direction impression knuckles per square inch that are raised above the plane of the fabric. These impression knuckles are created by an extra warp system that is "embroidered" onto a base fabric structure.
U.S. Pat. No. 5,429,686, issued Jul. 4, 1995 to Chiu, et al. for Apparatus for making soft tissue products discloses a TAD fabric having a load bearing layer and a sculpture layer. The high impression warp knuckles of this layer are created by effectively embroidering a second warp system onto a base fabric load bearing layer similar to the above-referenced patents to Wendt, et at.
U.S. Pat. No. 6,237,644, issued May 29, 2001 to Hay et al. for Tissue forming fabrics teaches a single layer lattice-shaped fabric of a design to form an embossed fibrous web. The lattice design is formed by the pattern of weaving of the single layer fabric, and requires no additional filaments or elements to form the embossed design.
U.S. Pat. No. 4,239,065, issued Dec. 16, 1980 to Trokhan for Papermachine clothing having a surface comprising a bilaterally staggered array of wicker-basket-like cavities teaches a fabric for making soft, absorbent paper of relatively low density, and relatively isotropic stretch properties when creped. The fabric is woven such that a top-surface plane is formed by coplanar crossovers of filaments and sub-top-surface crossovers are distributed in a predetermined pattern throughout the clothing.
U.S. Pat. No. 6,110,324, issued Aug. 29, 2000 to Trokhan, et al. for Papermaking belt having reinforcing piles teaches a fabric having yarns disposed, in part, to the top surface plane to form knuckles, and further including reinforcing piles that resist applied loads and may prevent deflection of the knuckles during the papermaking process.
U.S. Pat. No. 6,000,440, issued Dec. 14, 1999 to Hay for Multi-layer papermaking fabric teaches a multi-layer fabric with paperside to lower surface weft ratios greater than 1 and all paperside weft yarns interlacing with the warp yarns in an identical manner. The paperside weft yarns intermittently buttress against adjacent paperside weft yarns and possess an average lateral crimp ratio of greater than 1.62, producing a fabric having reduced fabric openness and thus an air permeability of less than 275 c.f.m./ft2 (cubic feet per minute per square foot) or about 4450 m3/m2/h (cubic meters per square meter per hour) at ½ inch water pressure. The fabric has a reduced rate of dewatering for increasing sheet smoothness, reducing two sidedness, providing additional sheet support, and reducing void volume for minimal sheet rewetting.
However, disadvantageously, TAD fabrics of the prior art have typically not provided an optimal relationship between fabric properties such as air permeability and warp fill, and finished paper sheet properties, namely paper sheet bulk. Ideally, the paper sheet bulk is maximized without slowing the paper machine or otherwise negatively affecting the paper machine running parameters or other sheet properties.
Thus, there remains a need for an improved through-air dryer (TAD) fabric, which fabric is woven according to a selected weave pattern from a system of synthetic monofilament warp and weft yarns which is chosen to provide a warp fill in the fabric of at least 100%, sufficient air permeability for producing relatively high drying rates, and a surface topography which will contribute to increased paper sheet bulk without adversely affecting other paper machine running parameters, in particular, machine speed.


An active vibration absorber including a frame connected to a structure to be controlled and at least two reaction mass elements operatively connected to the frame. Each of the reaction mass elements is independently movable with respect to said frame. The absorber includes a force generating member for controlling relative movement between the reaction mass elements for damping vibration of the structure. The inventive dual reactive mass absorber requires less control force to produce the same vibration attenuation as conventional single reactive mass absorbers.

1. Field of the Invention
The present invention generally relates to vibration absorbers and, more specifically, to an active dual mass absorber for vibration control.
2. Description of the Related Art
Dynamic passive vibration absorbers have been successfully used in industry to attenuate structural vibration for both narrow and broad-band excitations. The invention is directed to a device which is used in an active control methodology for damping vibrations (e.g., engine sounds and vibrations in aircraft, vibrations on buildings, vibrations emanating from power plants, etc.).
More recently, the performance of these passive devices has been enhanced through the addition of an active component. Currently available dynamic vibration absorbers utilize a single reaction mass connected to the structure to be controlled, wherein the active force is applied between the reaction mass and the structure to be controlled.
The active component in a conventional vibration absorber consists of a self-balanced force generating member applied between the absorber mass and the structure to be controlled. The force generating member generally exerts an equal force in opposite directions and could include any common device, such as piezoelectric patches, electromagnetic devices, and so forth. Such a conventional structure is sometimes referred to herein as a single mass (single reaction mass) absorber.
Such conventional hybrid passive/active dynamic vibration absorbers provide improved response attenuation over that achieved by the passive system at the expense of the energy added to the system via the control force. The required control effort is a function of both the absorber mass and the frequency tuning (i.e. the ratio of the absorber's frequency to the structure's natural frequency).
A detuned absorber requires larger control forces than a tuned absorber. In some applications, these drawbacks limit the implementation of hybrid absorbers due to constraints in size, weight, and/or required control force magnitudes.
FIG. 1 is a schematic illustration of a conventional single active dynamic vibration absorber ("DVA") or reaction mass system. This system consists of a single reaction mass 10 attached to the structure to be controlled 11, 14, 15 through a spring 12 and damper 13 system. The structure to be controlled may be represented by a mass-spring-damper system 11, 14, 15.
In the system illustrated in FIG. 1, an active force is applied by a force generating member 16 between the reaction mass 10 and the structure to be controlled 11. A motion sensor 17 detects the motion of the structure 11 and relays this information to the force generating member 16 via a filter compensator 19 and line 18.
In operation, a disturbance force F(t) acts on the structure 11. Motion sensor 17 senses the motion of structure 11 and, by an operation known as "feedback", supplies the force generating member 16 with a signal via filter 19 and line 18. Force generating member 16 applies equal and opposite forces to the reaction mass 10 and the structure 11 to eliminate the movement of member 11.
A similar operation known as "feedforward" is substantially similar to the feedback operation, except that the line 18 is connected to element causing the disturbance force F(t) (not illustrated) and the filter 19 is adjusted. The signal from the motion sensor 17 changes the force F(t) to damp the movement of the structure 11.

Active dual reaction mass absorber for vibration control

Virginia Tech Intellectual Properties, Inc.


A heat activatable adhesive composition including a thermoplastic resin, and a hindered phenol compound which is solid at 20xc2x0 C. and which is fusible at an elevated temperature. The adhesive composition is useful as a heat activatable adhesive layer of labels or sheets including a heat-sensitive recording label.

The present invention relates to a heat activatable adhesive composition and to an adhesive sheet or tape having an heat activatable adhesive layer.
Conventional adhesive sheets generally have a pressure-sensitive adhesive layer provided on a support with a liner (i.e., disposable backing sheet) being attached to the adhesive layer. In use, such a liner is removed and discarded. In view of problems caused by the use of liners, there are proposed adhesive sheets having a heat activatable adhesive layer but having no liner, that is, liner-free adhesive sheets.
The heat activatable adhesive layer is of a type which is not adhesive at room temperature but becomes adhesive when heated at an elevated temperature. The adhesive composition for use in the heat activatable adhesive layer is generally composed of a thermoplastic resin, a plasticizer and, optionally, a tackifier. The thermoplastic resin exhibits adhesiveness when plasticized. The plasticizer assumes a solid state at room temperature but is melted by the application of heat thereto to plasticize or swell the thermoplastic resin and to actualize the adhesiveness of the resin. The tackifier is used for improving the tackiness of the thermoplastic resin.
The heat activatable adhesive sheets are utilized in a wide variety of fields, for example, in the system of Point of Sales (POS) in which a heat activatable adhesive label is attached onto a wrapping film covering food. As the wrapping film, polyolefin films are substituted for conventional polyvinyl chloride films which cause environmental problems. Known heat activatable adhesive sheets, however, have a problem because its adhesion to polyolefin surfaces is not satisfactory.
JP-A-H09-265260 discloses an adhesive sheet including a substrate, an undercoat (heat insulation) layer provided on the substrate and containing hollow fine particles, a heat-sensitive recording layer provide on the undercoat layer, and a heat activatable layer provided on the substrate opposite the recording layer and containing dicyclohexyl phthalate as a plasticizer.
The conventional heat activatable adhesive sheet has another drawback that blocking phenomenon occurs when the sheet is stored in rolled form for a long period of time at a temperature of, for example, 40xc2x0 C. There is a demand for a heat activatable adhesive sheet which does not cause blocking at a temperature of 50xc2x0 C.
Known heat activatable adhesive sheets have a further problem because of the use of a phthalate as a plasticizer. The phthalate compounds are likely to adversely affect reproduction function through a food cycle.
It is, therefore, an object of the present invention to provide a heat activatable adhesive composition which can exhibit strong adhesiveness and excellent anti-blocking properties.
Another object of the present invention is to provide a heat activatable adhesive composition which can exhibit strong adhesiveness to polymer surfaces such as polyolefin surfaces.
It is a further object of the present invention to provide a heat activatable adhesive composition which does not contain a phthalate compound.
It is yet a further object of the present invention to provide a sheet having a heat activatable adhesive layer.
It is a further object of the present invention to provide sheet having (a) a heat activatable adhesive layer and (b) a heat-sensitive recording layer or an image receiving layer adapted for receiving an ink image transferred from an ink ribbon.
In accordance with the present invention there is provided a heat activatable adhesive composition comprising a thermoplastic resin, and a plasticizer including a hindered phenol compound which is solid at 20xc2x0 C. and which is fusible at an elevated temperature.
Other objects, features and advantages of the present invention will become apparent from the detailed description of the preferred embodiments of the invention to follow.
A heat activatable adhesive composition according to the present invention comprises a thermoplastic resin, a specific plasticizer and, optionally, a tackifier.
The thermoplastic resin is not particularly limited in the present invention, but the following polymeric resins can be preferably employed: a latex of natural rubber to which a vinyl monomer is graft-copolymerized, a natural rubber latex, polyvinyl acetate, polymethacrylate such as polybutyl methacrylate, synthetic rubber, vinyl acetate-2-ethylhexyl acrylate copolymer, vinyl acetate-ethylene copolymer, vinyl pyrrolidone-styrene copolymer, vinyl pyrrolidone-acrylate copolymer such as vinyl pyrrolidone-ethyl acrylate copolymer and styrene-acrylate compolymer. The amount of the thermoplastic resin in the adhesive composition is generally 10-70% by weight, preferably 20-60% by weight, for reasons of adhesiveness.
As the plasticizer, a hindered phenol compound which is solid at 20xc2x0 C. and which is fusible at an elevated temperature is used. The melting point of the hindered phenol compound is preferably at least 50xc2x0 C., more preferably at least 60xc2x0 C., for reasons of satisfactory anti-blocking property of an adhesive layer of the heat activatable adhesive composition. The upper limit of the melting point of the hindered phenol compound is preferably 150xc2x0 C. for reasons of heat sensitivity of the heat activatable adhesive layer.
The hindered phenol compound is preferably at least one compound selected from those represented by the following formulas (I) through (IV):
wherein R1, R2, R3, R4, R5, R6, R7, R9, and R10 independently stand for an alkyl group, and R8 and R11 each stand for a divalent hydrocarbyl group.
The alkyl groups R1, R2, R3, R4, R5, R6, R7, R9 and R10 each have preferably 1-20 carbon atoms, more preferably 1-12 carbon atoms. Most preferably, R1, R2, R4, R5, R6, R7, R9 and R10 are each xe2x80x94CH3 or xe2x80x94CH2H5 or an xcex1-branched alkyl group having 3-10 carbon atoms, such as tert-butyl, while R3 is a lower alkyl having 1-8 carbon atoms. Preferably, the divalent hydrocarbyl groups R8 and R11 are each an alkylene group having 1-12 carbon atoms.
The amount of the hindered phenol compound in the adhesive -composition is preferably 30-70% by weight, more preferably 35-65% by weight, for reasons of satisfactory adhesiveness.
In addition to the hindered phenol compound, the plasticizer can contain one or more conventional plasticizers, if desired. Examples of such conventional plasticizers include diphenyl phthalate, dihexyl phthalate, dicyclohexyl phthalate, dihydroabietyl phthalate, dimethyl isophthalate, sucrose benzoate, ethylene glycol dibenzoate, trimethylolethane tribenzoate, glyceride tribenzoate, pentaerythritol tetrabenzoate, sucrose octacetate, tricyclohexyl citrate and N-cyclohexyl-p-toluene-sulfonamide. The amount of the plasticizer in the adhesive composition is preferably in the range of 30 to 70% by weight, more preferably in the range of 35 to 65 wt % by weight, of the total weight of the adhesive composition for reasons of satisfactory adhesiveness of the adhesive composition.
It is preferred that the adhesive composition contain a tackifier for reasons of improved adhesiveness of thereof. The tackifier preferably has a melting point or softening point of at least 70xc2x0 C., more preferably 70-200xc2x0 C. for reasons of satisfactory anti-blocking property of a heat activatable adhesive layer formed of the adhesive composition. Examples of suitable tackifier include rosins and derivatives thereof (such as polymerized rosin, hydrogenated rosin, esters of the above-mentioned rosins with polyhydric alcohols such as glycerin and pentaerythritol, and diners of resin acid); terpene resins; petroleum resins; phenolic resins; and xylene resins. The tackifier is used in an amount of 3 to 30% by weight, more preferably 5 to 25% by weight based on the total weight of the adhesive composition.
In one embodiment of the present invention, the heat activatable adhesive composition is used for a label or sheet including a substrate and an adhesive layer of the heat activatable adhesive composition provided on a surface of the substrate.
In another embodiment of the present invention, the heat activatable adhesive composition is used for a heat-sensitive recording label or sheet. The label includes a substrate, a heat-sensitive recording layer provided on one surface of the substrate, and an adhesive layer of the heat activatable adhesive composition provided on the other surface of the substrate.
The heat-sensitive recording layer contains one or more leuco dyes as a coloring agent. Suitable leuco dyes for use in the coloring layer, which may be employed alone or in combination, include any known leuco dyes for use in the conventional thermosensitive recording materials. For example, triphenylmethane-type leuco compounds, fluoran-type leuco compounds, phenothiazine-type leuco compounds, auramine-type leuco compounds, spiropyran-type leuco compounds, and indolinophthalide-type leuco compounds are preferably employed.
Specific examples of such leuco dyes include:
3,3-bis(p-dimethylaminophenyl)phthalide,
3,3-bis(p-dimethylaminophenyl)-6-dimethylaminophthalide (i.e., Crystal Violet Lactone),
3,3-bis p-dimethylaminophenyl)-6-diethylaminophthalide,
3,3-bis(p-dimethylaminophenyl)-6-chlorophthalide,
3,3-bis(p-dibutylaminophenyl)phthalide,
3-cyclohexylamino-6-chlorofluoran,
3-dimethylamino-5,7-dimethylfluoran,
3-diethylamino-7-chlorofluoran,
3-diethylamino-7-methylfluoran,
3-diethylamino-7,8-benzfluoran,
3-diethylamino-6-methyl-7-chlorofluoran,
3-(N-p-tolyl-N-ethylamino)-6-methyl-7-anilinofluoran,
3-pyrrolidino-6-methyl-7-anilinofluoran,
2-[N-(3xe2x80x2-trifluoromethylphenyl)amino]-6-diethylaminofluoran,
2-[3,6-bis(diethylamino)-9-(o-chloroanilino)xanthyl]-benzoic acid lactam,
3-diethylamino-6-methyl-7-(m-trichloromethylanilino)fluoran,
3-diethylamino-7- (o-chloroanilino) fluoran,
3-di-n-butylamino-7-(o-chloroanilino)fluoran,
3-(N-methyl-N-n-amylamino)-6-methyl-7-anilinofluoran,
3-(N-methyl-N-cyclohexylamino)-6-methyl-7-anilinofluoran,
3-diethylamino-6-methyl-7-anilinofluoran,
3-(N, N-diethylamino)-5-methyl-7-(N,N-dibenzylamino)fluoran, benzoyl leuco methylene blue,
6xe2x80x2-chloro-8xe2x80x2-methoxybenzoindolino spiropyran,
6xe2x80x2-bromo-3xe2x80x2-methoxybenzoindolino spiropyran,
3-(2xe2x80x2-hydroxy-4xe2x80x2-dimethylaminophenyl)-3-(2xe2x80x2-methoxy-5xe2x80x2-chlorophenyl)phthalide,
3-(2xe2x80x2-hydroxy-4xe2x80x2-dimethylaminophenyl)-3-(2xe2x80x2-methoxy-5xe2x80x2-nitrophenyl)phthalide,
3-(2xe2x80x2-hydroxy-4xe2x80x2-diethylaminophenyl)-3-(2xe2x80x2-methoxy-5xe2x80x2-methylphenyl)phthalide,
3-diethylamino-6-methyl-7-(2xe2x80x2,4xe2x80x2-dimethylanilino)fluoran,
3-(2xe2x80x2-methoxy-4xe2x80x2-dimethylaminophenyl)-3-(2xe2x80x2-hydroxy-4xe2x80x2-chloro-5xe2x80x2-methylphenyl) phthalide,
3,6-bis(dimethylamino)fluorenespiro(9,3xe2x80x2)-6xe2x80x2-dimethylaminophthalide,
3-(p-dimethylaminophenyl)-3-{1,1-bis(p-dimethylaminophenyl)ethylene-2-yl}phthalide,
3-(p-dimethylaminophenyl)-3-{1,1-bis(p-dimethylaminophenyl)ethylene-2-yl}-6-dimethylaminophthalide,
3-(p-dimethylaminophenyl)-3-(1-p-dimethylaminophenyl)-1-phenylethylene-2-yl}phthalide,
3-(p-dimethylaminophenyl)-3-(1-p-dimethylamino-1-p-chlorophenylethylene-2-yl}-6-dimethylaminophthalide,
3-(4xe2x80x2-dimethylamino-2xe2x80x2-methoxy)-3-(1xe2x80x3-p-dimethylaminophenyl-1xe2x80x3-p-chlorophenyl-1xe2x80x3,3xe2x80x3-butadiene-4xe2x80x3-yl)benzophthalide,
3-(4xe2x80x2-dimethylamino-2xe2x80x2-benzyloxy)-3-(1xe2x80x3-p-dimethylaminophenyl-1xe2x80x3-phenyl-1xe2x80x3,3xe2x80x3-butadiene-4xe2x80x3-yl)benzophthalide,
3-dimethylamino-6-dimethylaminofluorene-9-spiro-3xe2x80x2-(6xe2x80x2-dimethylaminophthalide,
3,3-bis{2-(p-dimethylaminophenyl)-2-(p-methoxyphenyl)ethenyl}4,5,6,7-tetrachlorophthalide,
3-bis{1,1-bis(4-pyrrolidinophenyl)ethylene-2-yl-5,6-dichloro-4,7-dibromophthalide, bis(p-dimethylaminostyryl)-1-naphthalenesulfonylmethane,
3-(N-ethyl-N-tetrahydrofurfurylamino)-6-methyl-7-anilinofluoran,
3-(N-ethyl-N-2-ethoxypropylamino)-6-methyl-7-anilinofluoran,
3-N-methyl-N-isobutyl-6-methyl-7-anilinofluoran,
3-morphorino-7-(N-propyltrifluoromethylanilino)fluoran,
3-pyrrolidino-7-trifluoromethylanilinofluoran,
3-diethylamino-5-chloro-7-(N-benzyltrifluoromethylanilino)fluoran,
3-pyrrolidino-7-(di-p-chlorophenyl)methylaminofluoran,
3-diethylamino-5-chloro-7-(xcex1-phenylethylamino)fluoran,
3-(N-ethyl-p-toluidino)-7-(xcex1-phenylethylamino)fluoran,
3-diethylamino-7-(o-methoxycarbonylphenylamino)fluoran,
3-diethylamino-5-methyl-7-(xcex1-phenylethylamino)fluoran,
3-diethylamino-7-piperidinofluoran,
2-chloro-3-(N-methyltoluidino)-7-(p-n-butylanilino)fluoran,
3-(N-methyl-N-isopropylamino)-6-methyl-7-anilinofluoran,
3-di-n-butylamino-6-methyl-7-anilinofluoran,
3-(N-benzyl-N-cyclohexylamino)-5,6-benzo-7-xcex1-naphthylamino-4xe2x80x2-bromofluoran,
3-diethylamino-6-chloro-7-anilinofluoran,
3-diethylamino-6-methyl-7-mesidino-4xe2x80x2,5xe2x80x2-benzofluoran,
3-N-methyl-N-isopropyl-6-methyl-7-anilinofluoran,
3-N-ethyl-N-isoamyl-6-methyl-7-anilinofluoran, and
3-diethylamino-6-methyl-7-(2xe2x80x2,4xe2x80x2-dimethylanilino)fluoran.
The heat-sensitive recording layer also contains a developer. Any conventional electron acceptor or oxidizing agent which works upon the above-mentioned leuco dyes to induce color formation, such as phenol compounds, thiophenol compounds, thiourea compounds, organic acids and metal salts of organic acids, can be employed. Specific examples of such color developers include:
4,4xe2x80x2-isopropylidenediphenol,
3,4xe2x80x2-isopropylidenebisphenol,
4,4xe2x80x2-isopropylidenebis(o-methylphenol),
4,4xe2x80x2-sec-butylidenebisphenol,
4,4xe2x80x2-isopropylidenebis(2-tert-butylphenol),
2,2xe2x80x2-methylenebis(4-ethyl-6-tert-butylphenol), zinc p-nitrobenzoate,
1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimetylbenzyl)-isocyanuric acid,
2,2-(3,4xe2x80x2-dihydroxydiphenyl)propane,
11,3-bis(4-hydroxyphenylthio)-2-hydroxypropane,
5bis(4-hydroxy-3-methylphenyl)sulfide,
4-[xcex2-(p-methoxyphenoxy)ethoxy]salicylate,
1,7-bis(4-hydroxyphenylthio)-3,5-dioxaheptane,
1,5-bis(4-hydroxyphenylthio)-5-oxapentane, monocalcium salt of monobenzylphthalate,
4,4xe2x80x2-cyclohexylidenediphenol,
4,4xe2x80x2-isopropylidenebis(2-chlorophenol),
2,2xe2x80x2-methylenebis(4-methyl-6-tert-butylphenol),
4,4xe2x80x2-butylidenebis(6-tert-butyl-2-methyl)phenol,
1,1,3-tris(2-methyl-4-hydroxy-5-tert-butylphenyl)butane,
1,1,3-tris(2-methyl-4-hydroxy-5-cyclohexylphenyl)butane,
4,4xe2x80x2-thiobis(6-tert-butyl-2-methyl)phenol,
4,4xe2x80x2-diphenolsulfone,
4,2xe2x80x2-diphenolsulfone,
4-isoproxy-4xe2x80x2-hydroxydiphenylsulfone,
20 4-benzyloxy-4xe2x80x2-hydroxydiphenylsulfone,
4,4xe2x80x2-diphenolsulfoxide,
isopropyl p-hydroxybenzoate,
benzyl p-hydroxybenzoate,
benzyl protocatechuate,
stearyl gallate,
lauryl gallate,
octyl gallate,
1,3-bis(4-hydroxyphenylthio)propane,
N,Nxe2x80x2-diphenylthiourea,
N,Nxe2x80x2-di(m-chlorophenyl)thiourea,
salicylanilide,
5-chlorosalicylanilide,
salicyl-o-chloroanilide,
bis(4-hydroxyphenyl)methyl acetate,
bis(4-hydroxyphenyl)benzyl acetate,
1,3-bis(4-hydroxycumyl)benzene,
1,4-bis(4-hydroxycumyl)benzene,
2,4xe2x80x2-diphenolsulfone,
3,3xe2x80x2-diallyl-4,4xe2x80x2-diphenolsulfone,
3,4-dihydroxy-4-methyldiphenylsulfone,
antipyrin complex of zinc thiocyanate,
2-hydroxy-3-naphthoic acid,
2-hydroxy-1-naphthoic acid,
1-hydroxy-2-naphthoic acid,
metal(zinc, aluminum, calcium, etc.) salts of hydroxynaphthoic acid,
zinc 1-acetyloxy-2-naphthoate,
zinc 2-acetyloxy-1-naphthoate,
zinc 2-acetyloxy-3-naphthoate,
xcex1,xcex1bis(4-hydroxyphenyl)-xcex1-methyltoluene,
tetrabromobisphenol A,
tetrabromobisphenol S,
4,4xe2x80x2-thiobis(2-methylphenol), and
4,4xe2x80x2-thiobis(2-chlorophenol).
These developers are employed alone or in combination.
The developer is used in an amount of from about 1 to about 20 parts, more preferably from about 2 to about 10 parts by weight, per 1 part by weight of the coloring agent.
The heat-sensitive recording layer further contains a binder resin. Any conventionally employed binder such as a water-soluble polymer may be suitably used for the purpose of the present invention. Examples of binder resins include polyvinyl alcohol starch and starch derivatives cellulose derivatives such as methoxy cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose and ethyl cellulose, sodium polyacrylate, polyvinyl pyrrolidone, acrylamide-acrylic ester copolymer, acrylamide-acrylic ester-methacrylic acid terpolymer, alkali salts of styrene-maleic anhydride copolymer, polyacrylamide, sodium alginate, gelatin and casein. An aqueous polymer emulsion of polyvinyl acetate, polyurethane, polyacrylic acid, polyacrylate, polymethacrylate, polybutylmethacrylate, vinyl chloride-vinyl acetate copolymer or ethylene-vinyl acetate copolymer, or a latex of styrene-butadiene copolymer and styrene-butadiene-acrylic copolymer may also be used as the binder.
The heat-sensitive recording layer may contain a heat-fusible material preferably having a melting point of 50-200xc2x0 C. Illustrative of suitable heat-fusible material are fatty acids such as stearic acid and behenic acid; fatty acid esters; fatty amides such as stearamide and palmitamide; fatty acid salts such as zinc stearate, calcium stearate, aluminum stearate, zinc plamitate and zinc behenate; and waxes such as stearate wax, polyethylene wax, carnauba wax, licrocrystalline wax and carboxyl-modified paraffin wax. Other suitable heat-fusible materials include p-benzylbiphenyl, terphenyl, triphenylmethane, benzyl p-benzyloxybenzoate, xcex2-benzyloxynaphthalene, phenyl xcex2-naphthoate, phenyl 1-hydroxy-2-naphthoate, methyl 1-hydroxy-2-naphthoate, diphenyl carbonate, glycol carbonate, dibenzyl terephthalate, dimethyl terephthalate, 1,4-dimethoxynaphthalene, 1,4-diethoxynaphthalene, 1,4-dibenzyloxynaphthalene, 1,2-diphenoxyethane, 1,2-bis(3-methylphenoxy)ethane, 1,2-bis(4-methylphenoxy)ethane, 1,4-diphenoxy-2-butene, 1,2-bis(4-methoxyphenylthio)ethane, dibenzoylmethane, 1,4-diphenylthiobutane, 1,4-diphenylthio-2-butene, 1,3-bis(2-vinyloxyethoxy) benzene, 1-4-bis(2-vinyloxyethoxy)benzene, p-(2-vinyloxyethoxy)biphenyl, p-allyloxybiphenyl, p-propagyloxybiphenyl, dibenzoyloxymethane, dibenzoyloxypropane, dibenzyldisulfide, 1,1-diphenylethanol, 1,1-diphenylpropanol, p-benzyloxybenzyl alcohol, 1,3-phenoxy-2-propanol, N-octadecylcarbamoyl-p-methoxycarbonylbenzene, N-octadecylcarbamoylbenzene, 1,2-bis(4-methoxyphenoxy)propane, 1,5-bis(4-methoxyphenoxy)-3-oxapentane, dibenzyl oxalate, di-p-methylbenzyl oxalate or di-4-chlorobenzyl oxalate.
The heat-sensitive recording layer may additionally contains various conventionally employed additives such as a surfactant, an organic or inorganic filler and a lubricant. Examples of fillers include silica, zinc oxide, aluminum hydroxide, zinc hydroxide, barium sulfate, kaolin, clay, talc, calcium carbonate, magnesium carbonate, calcined clay, titanium oxide, diatomaceous earth, anhydrous silica, activated clay, surface treated calcium, styrene-methacrylic acid copolymer powder, nylon powder, polyethylene powder, polystyrene powder and urea-formaldehyde resin powder.
The heat-sensitive recording layer may be formed on a substrate by any customarily employed method. For example, the above-described leuco dye, developer and an aqueous solution or dispersion of a binder are ground with a ball mill, an attriter or a sand mill into a particle size of 1-3 xcexcm. The resulting dispersion is then mixed with other additives such as a filler and a heat-fusible material to obtain a coating liquid. The coating liquid is applied onto the substrate and dried to form the heat-sensitive recording layer thereon.
If desired, an undercoating layer may be interposed between the substrate and the heat-sensitive layer. An protecting layer (overcoat layer) may also be formed over the heat-sensitive layer. Such undercoating and protecting layers may be constituted of the above-described binder resin and, optionally, filler, heat-fusible material and surfactant. If desired an ink image may be printed on the heat-sensitive recording layer or on the protecting layer. The ink may be, for example, a UV-curable ink.
In a further embodiment of the present invention, the heat activatable adhesive composition is utilized for a heat transfer recording label or sheet including a substrate, an image receiving or accepting layer provided on one surface of the substrate and an adhesive layer of the heat activatable adhesive composition provided on the other surface of the substrate. The image receiving layer is adapted to receive an ink image, by fusion or sublimation transfer, from an ink ribbon which is heated imagewise with a thermal head.
The image receiving layer generally contains a filler and a binder. A water-resistance imparting agent such as a crosslinking agent may be also incorporated into the ink receiving layer.
Examples of the fillers for use in the image receiving layer include inorganic pigments such as calcium carbonate, silica, zinc oxide, titanium oxide, aluminum oxide, aluminum hydroxide, zinc hydroxide, barium sulfate, clay, calcined clay, magnesium silicate, magnesium carbonate, white carbon, kaolin, talc, surface treated calcium carbonate and silica; and organic pigments such as urea-formaldehyde resins, styrene-methacrylic acid copolymers, polystyrene resins.
Suitable binders for use in the image receiving layer include water soluble resins such as polyvinyl alcohol; starch and derivatives thereof; cellulose derivatives such as methoxy cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose and ethyl cellulose; sodium polyacrylate; polyvinyl pyrrolidone; acrylamide-acrylate copolymers; acrylamide-acrylate-methacrylic acid copolymers; styrene-maleic anhydride alkali metal salts; isobutylene-maleic anhydride alkali metal salts; polyacrylamide; sodium alginate; gelatin; and casein. The binder is generally used in an amount of 0.1 to 0.2 part by weight per part by weight of the filler.
Illustrative of suitable water-resistance imparting agent are formaldehyde, glyoxal, chromium alum, melamine-formaldehyde resins, urea resin, melamine resin, polyamide resins and polyamide-epichlorohydrin resins. The water-resistance imparting agent is generally used in an amount of 0.3 to 0.5 part by weight per part by weight of the binder. The image receiving layer is preferably treated by calendaring to have a surface smoothness of 500 seconds or more for reasons of improved grade of the images.
In a further embodiment of the present invention, the heat activatable adhesive composition is utilized for a double coated adhesive sheet having a substrate and adhesive layers of the adhesive composition formed on both sides of the substrate.
In the foregoing embodiments, a heat insulating layer may be suitably interposed between the substrate and the adhesive layer of the heat activatable adhesive composition for the purpose of improving efficiency in being heated. Such a heat insulating layer may also be interposed, as an undercoat layer, between the substrate and the heat-sensitive recording layer for the purpose of improving heat-sensitivity thereof.
In the present invention, there can be employed (a) a non-expanded insulating layer using (a1) minute void particles with a voidage of 30% or more, each made of a thermoplastic resin as its shell or (a2) a porous pigment; and (b) an expanded insulating layer containing an expanded filler.
The minute void particles with a voidage of 30% or more for use in the former-type insulating layer are minute particles expanded so that air or other gases are contained therewithin. The minute void particles with an average particle size of 2 to 20 xcexcm, preferably 3 to 10 xcexcm are employed. When the average particle diameter (outer diameter) of the minute void particles is 2 xcexcm or less, void particles with a desired voidage cannot be easily produced. When the average particle diameter of the minute void particles is 20 xcexcm or more, the surface smoothness of the obtained insulating layer is lowered. It is preferred that the minute particles be classified to have a uniform particle size.
The voidage of the minute void particles for use in the insulating layer is 30% or more, preferably 50% or more. When the insulating layer interposed between the support and the heat activatable adhesion layer has a voidage of 30% or less, sufficient insulating properties cannot be obtained, so that the thermal energy applied to the adhesive layer by a heating medium for heat activation cannot be efficiently used for heat activation thereof and, hence, improvement in adhesion cannot be attained.
The term xe2x80x9cvoidagexe2x80x9d of minute void particles herein is intended to refer to a percentage obtained by the following formula:
Voidage (%)=DI/DOxc3x97100
wherein DI and DO represent the inner and outer diameters of the void particles, respectively.
The minute void particles are formed of a thermoplastic resin which constitutes shells thereof, as previously mentioned. As the above-mentioned thermoplastic resin, a copolymer resin containing as major components vinylidene chloride and acrylonitrile is preferably employed.
Examples of the porous pigment for use in the non-expanded insulating layer include organic pigments such as urea-formaldehyde resin, and inorganic pigments such as shirasu clay.
The non-expanded insulating layer may be formed on the substrate as follows. The above-mentioned minute void particles or porous pigment particles are dispersed in water together with a binder to obtain a coating liquid. The coating liquid thus prepared is then coated on the substrate and dried to obtain the insulating layer formed on the substrate. In this case, the deposition amount of the minute void particles is preferably at least 1 g/m2, more preferably in the range of about 2 to 15 g/m2. The binder is generally used in an amount of 2 to 50% by weight based on the total weight of the minute void particles and the binder.
As the binder for the non-expanded insulating layer, a water-soluble polymer or an aqueous polymer emulsion is preferably used. Illustrative of suitable water-soluble polymers are polyvinyl alcohol, starch and starch derivatives, cellulose derivatives such as methoxy cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose and ethyl cellulose, sodium polyacrylate, polyvinyl pyrrolidone, acrylamide-acrylic ester copolymer, acrylamide-acrylic ester-methacrylic acid terpolymer, alkali salts of styrene-maleic anhydride copolymer, polyacrylamide, sodium alginate, gelatin and casein. Illustrative of suitable aqueous polymer emulsions are latexes such as styrene-butadiene copolymer and styrene-butadiene-acrylic copolymer and emulsions such as vinyl acetate resin, vinyl acetate-acrylic acid copolymer, styrene-acrylate copolymer, acrylate resin and polyurethane resin.
An expandable filler is used for formation of the expandable insulating layer. The expandable filler may be plastic void filler particles, each having a thermoplastic resin shell and a blowing agent, such as a low boiling point solvent, contained in the shell. The void plastic filler particles thus constructed are expanded when heated. It is preferred that the particle size of expandable plastic filler be in the range of 2 to 50 xcexcm, more preferably 5 to 20 xcexcm, in the non-expanded state, and in the range of 10 to 100 xcexcm, more preferably 10 to 50 xcexcm, in the expanded state.
Examples of the thermoplastic resins for forming the shell of the expandable plastic filler particles include polystyrene, polyvinyl chloride, polyvinylidene chloride, polyvinyl acetate, polyacrylate, polyacrylonitrile, polybutadiene and copolymers comprising monomers constituting the above-mentioned resin. As the blowing agent, propane, butane or a mixture thereof is generally employed.
The expanded insulating layer may be formed on the support as follows. A mixture of the above-mentioned expandable plastic filler and a binder is coated on the support and dried to obtain a coating. Then, the coating is contacted with a hot plate to expand the expandable filler. It is preferred that the deposition amount of the plastic filler be at least 1 g/m2, more preferably about 2 to 5 g/m2 in a non-expanded state. The binder may be added to the plastic filler in such an amount that can firmly bind the obtained expandable insulating layer to the support. In general, the amount of the binder is in the range of 5 to 50% by weight based on the total weight of the expandable plastic filler and the binder agent. The blowing temperature of the plastic filler is a softening point of the thermoplastic resin constituting the shell of the plastic filler particles. It is preferred that the blowing magnification be 2 to 4 times, more preferably 2 to 3 times.
The surface of the obtained insulating layer of an expanded type is considerably rough. Therefore, it is preferable to subject the insulating layer to a surface treatment by calendaring after expanding the plastic filler particles bye the application of heat thereto. When necessary, at least one undercoat layer may be provided on the insulating layer. Such an undercoat may also be provided under the insulating layer.
The above-mentioned insulating layer may further comprise auxiliary additives, such as a filler, a heat-fusible material and a surfactant. The filler and heat-fusible material previously described with regard to the heat-sensitive layer may also used for the insulating layer.
The substrate used in the foregoing embodiments may be any conventionally employed support such as paper (e.g. woodfree paper, art paper or coated paper) or a plastic film (e.g. a polyester film made of polyethylene terephthalate or polybutylene terephthalate, a cellulose derivative film made of cellulose triacetate, a polyolefin film made of polypropylene or polyethylene, a polystyrene film or a laminated film of the above-mentioned films).
The following examples will further illustrate the present invention. Parts and percentages are by weight.

Heat activatable adhesive composition and adhesive sheet having adhesive layer thereof


An induction furnace apparatus and method for reducing the magnetic field produced by the operation of the furnace. The induction furnace including a refractory vessel, an induction coil, and an outer shell having a layer of metallic and magnetically permeable material. The metallic and magnetically permeable material comprising a plurality of elements having a shape and size that is chosen to maximize the packing density of elements throughout the layer. The outer shell further including a top, base, and sidewall arranged about the refractory vessel such that the metallic and magnetically permeable material is formed between the refractory vessel and the outer shell. The invention provides a method for casting metallic and magnetically permeable material with or without a non-conductive matrix. The castings can be formed into inserts or incorporated into the top, base, and side wall of the outer shell. The invention includes inserts comprising metallic and magnetically permeable material located in a space formed between the refractory vessel and the outer shell.

An induction furnace employs electromagnetic energy to induce electrical currents to flow within a charge of metal or metal alloy. The electrical resistance of the metal produces heat as a natural consequence of the induced currents flowing in the metal. The combination of applied electrical power and frequency can be chosen to create sufficient heat within the metal to cause it to melt. The molten metal can then be poured into molds or otherwise used to produce a wide variety of metal products.
The basic elements of an induction furnace include an electro-magnetic induction coil, a vessel having a lining of refractory material, and a structure for supporting the induction coil and vessel. The induction coil comprises an electrical conductor of sufficient size and current capacity to produce the magnitude of magnetic flux necessary to induce large currents in the metal charge. The magnetic flux represents the lines of force of a magnetic field. The magnetic field emanates from the furnace and surrounds the adjacent work area occupied by operating personnel and equipment.
There is a need to reduce the magnetic fields produced by the operation of induction furnaces. Although the health consequence resulting from exposure to magnetic fields is unknown, it is deemed prudent to provide a design and method for magnetic field reduction. However, it is well known that EMI (electromagnetic interference) can cause failure or destruction of electronic equipment resulting from exposure to high energy magnetic fields. Therefore, there is a need to protect operating personnel and equipment from magnetic field exposure caused by the operation of an induction furnace.


The present invention provides electronic methods and apparatus for storing and organizing access to restricted multimedia objects. This is accomplished using semantic networks by interactively defining a semantic network, identifying a relationship between nodes by associating a label with each semantic link, attaching multimedia objects to nodes and restricting user access to multimedia objects and/or the semantic network. The method allows users to access and edit the semantic network in a Java- or AJAX-based platform-independent software environment. The present invention further provides a method for rating semantic networks by allowing viewers to provide feedback regarding a semantic network's value or usefulness and then calculating a rating in accordance with the received feedback. The present invention further provides a method for linking semantic networks to build a knowledge base.

Conventionally, users have been required to organize multimedia materials, such as image files, video clips, audio clips, and source documents, using tree-like directories with folders (e.g., Microsoft Windows). Nevertheless, recent research has revealed the power of using more flexible, non-hierarchical graphs or networks to organize materials, such as a concept map or semantic network. See, e.g., U.S. Pat. No. 5,506,937, "Concept Mapbased Multimedia Computer System for Facilitating User Understanding of a Domain of Knowledge," University of West Florida (the "'937 patent").
However, existing non-hierarchical systems, such as the system described in the '937 patent, have not adequately addressed the dimension of multiple-user, network-based collaborative authoring and viewing. For example, the '937 patent fails to provide simultaneous multi-user viewing and editing, restricted-access user privileges, and shared network libraries and resources. Moreover, it is desirable that such capabilities are provided in a light-weight, platform-independent software environment while incorporating an intuitive, informative, and well-integrated user interface.

Methods and apparatus for storing, organizing, sharing and rating multimedia objects and documents

The Board of Trustees of the Leland Stanford Junior University


A hand operated fruit squeezer includes a first squeezer member having a hand grip portion, a pivot portion, and a substantially rounded receptacle portion having a bottom with apertures; a second squeezer member having a hand grip portion, a pivot portion, and a substantially rounded head portion with a pair of presses that fittingly correspond downward into the receptacle portion of the first squeezer member; and a blade assembly pivotally arranged between the first squeezer member and the second squeezer member to hold a fruit in a position suitable for cutting, and squeezing. The first squeezer member, the second squeezer member, and the blade assembly are pivotally coupled using a pivot means that engages into the pivot portions of the first squeezer member, the second squeezer member, and the blade assembly to make the hand operated fruit squeezer operational.

The juice from citrus fruits, such as lemons or limes is very useful and is used as a popular ingredient for sauces, drinks, glazes, marinades, custards, and for salad dressings. The citrus juice is widely utilized by consumers for personal use or by restaurants, and the like facilities. The juice is typically squeezed from sliced pieces of lemon by hand into a bowl or like container or directly over a prepared platter of food. However, squeezing juice from the fruit such as lemon by hand is often difficult, time-consuming and messy and can result in un-squeezed juice remaining in the lemon. In addition, squeezing fruit by hand may cause bacteria, germs and dirt particles to contaminate the juice if hands were not properly cleaned. Further, squeezing the fruit using hand results in fruit pulp and pits also being squeezed from the fruit and falling into the food or beverage which then requires the removal of these elements from the juice.
One of popular conventional hand operated fruit squeezer includes a shallow container, a plurality of apertures formed on the bottom of the shallow container, and a protruding element mounted on the surface of the shallow container for being inserted into a cross-section of the cut fruit. When the fruit is pressed on the protruding element by the applied force, the fruit juice is squeezed out of the fruit. However, since fruits such as oranges and lemons contain the fruit stems that interfere with the process of squeezing the soft and dense fruit pulp. Many a times, the fruit juice cannot be fully squeezed out of the fruit pulps and lots of energy of the user is wasted on applying the force.
Several prior art fruit squeezers have attempted to resolve above discussed issues. However, the prior art fruit squeezers are cumbersome to use, often require two hands to manipulate the squeezer with lot of force, and most importantly they require additional tools, such as knives or blades for slicing the fruits prior to squeezing.
Examples of the prior art lemon squeezers may be seen in U. S. Pat. Pub. No. 20130186289 to Fernando Garcia that discloses a lemon juicer device to juice a half lemon.
U.S. Pat. No. 2,348,304 to C. S. Nudelman et al that discloses a serving and squeezing device for citrus fruits that operates upon the slices of citrus fruits.
U. S. Pat. No. 9,095,169 to Foley et al that discloses a hand operable juicer that requires a half fruit, such as an orange cut in half, and placing and pressing the half fruit on a pulping crown.
Finally, a hand-operated rotary fruit juice extractor may be seen in U. S. Pat. No. 2,443,129 which provides a squeezing and turning device that takes half lemon or orange as input and the device is turned by use of one hand by the user while suitable pressure for squeezing is applied by the user using other hand.
All of these devices involve uses of additional tools, such as the knives or blades for slicing or segmenting the citrus fruits prior to squeezing. Further, many of these are heavy and cumbersome designs to operate.
Inventors have also envisioned the squeezers that may not require additional cutting tools for slicing the citrus fruits prior to squeezing, one of the prior arts related to such hand operated lemon squeezers is MX2013000423 that relates to a manual hand squeezer with a cradle or cup part that holds the lemon or citrus fruit and the cradle part consists of an integrated knife for slicing the lemon in one movement when the user actuates the lever containing a crusher that correspond to the cradle or the cup; Another, existing prior art U. S. Pat. No. 1,762,031 by James H Roberts discloses about a squeezer that simultaneously cuts and squeezes fruits to eliminate usual necessity of cutting the fruit into halves prior to squeezing of the fruits. As disclosed in the patent, the device includes two hinged handle members, a top handle member that includes a rounded semicircular spaced parallel plunger member, and a down handle member with a cup-shaped receptacle provided immediately underneath the plunger member. The bottom of the receptacle is reticulated with a blade fitted within the receptacle.
The devices presented in MX2013000423 and U. S. Pat. No. 1,762,031 do tend to eliminate necessity of additional tools for cutting or slicing the lemon or the like fruit prior to squeezing as cutting feature is embedded in the squeezer itself, however, such devices are unsafe for regular cleaning and for regular operation. For example, it is likely possible that when the user cleans the inner bowl or receptacle containing remains of squeezed lemons or like fruits, their fingers might come in contact with sharp edges of the blades fixedly mounted inside the interior cavity of the cup-shaped receptacle holding the remains of squeezed lemons. This is also true when washing the device, since cleaning the interior receptacle might be unsafe without the ability to get the blade out of the way. Further, such proposed solutions are restrictive in their applications, for example, sometimes the fruit sizes can vary and at such instances the proposed solutions fail to properly function.
Additionally, many times, the users of the citrus juicers may need to grate skin of lemons or the like fruits as skin of such fruits contain aromatic substances and vitamin components, especially during drink preparation. However, at times, graters or rinders suitable for use are not readily available when the users need them.
Thus, in the light of the above-mentioned background art, it is evident that, there is a need for an ergonomic hand operated fruit squeezer that would facilitate the users to more comfortably and rapidly cut and squeeze the citrus fruits in one motion, without the need for additional cutting tools. Next, the present invention is directed towards the hand operated fruit squeezer that helps mitigate any risk associated with cleanliness of the squeezers. Next, the objective of the present invention is to provide the fruit squeezer that has an ergonomic design that can help user to operate the device with lesser efforts by applying pressure using one hand. Next, the objective of the present invention is to provide the hand operated squeezer that may be suitable for varying sizes of the lemon or the like fruit.


Loss circulation fluids contain aqueous based compositions having at least one alkali metal formate and at least one thermally activated self-crosslinkable gel forming material, wherein the composition is easily transported to a loss circulation zone and yet has ability to close off the loss circulation zone once thermally activated to reduce the loss of circulation fluids into flow passages of a subterranean formation. In addition, packer fluids contain aqueous based compositions which contain at least one alkali metal formate and at least one thermally activated self-crosslinkable gel forming material, wherein the packer fluid forms a thermal insulating fully hydrated gel once thermally activated.

The present invention relates to weighted zero solids loss circulation and/or fluid loss systems, such as for the drilling industry, like oil field drilling and completion operations.
In one or more embodiments, the present invention relates to loss circulation fluids or loss circulation drilling fluids, and methods to control loss circulation fluids.
In the drilling of well bores with modern rotary well drilling apparatus and methods, the bore hole is normally kept filled with clean circulating drilling mud, or other drilling fluid, which washes and flushes the cuttings removed by the rotary bit from the bottom of the well bore. Drilling muds, or other drilling fluids, are pumped under pressure down the interior of the drill pipe and are forced out through openings in the drill bit, providing lubrication and wetting of the exposed surface, which increases the efficiency of the bit. The fluid then lifts the rock cuttings produced by the bit away from it and carries them up the annulus outside the string of drill pipe.
As the drilling mud, or other drilling fluid, passes up the annulus, it deposits a film or cake on the walls of the surrounding formation. This film or cake serves to seal small cracks or fissures, circa. 0.001-0.002″ size, in the formation and also decreases friction on the rotating string of drill pipe. The rock cuttings which are carried to the surface by the drilling mud, or other drilling fluid, are removed from the mud, or other drilling fluid, by various types of separators, e.g. shaker screens, centrifugal filtering systems, desilters, etc. The cleaned drilling mud, or other drilling fluid, is then recirculated.
Conventional drilling muds, or other drilling fluids, are of varied composition, depending upon the needs of the particular drilling operation. While most drilling muds are mixtures of fresh water with various clays, such as expansible bentonite clay, native clay and attapulgite clay, such muds may contain salt water, oil, oil emulsions, synthetic materials, such as polymeric additives, or combinations of such materials. The term "drilling mud", as used herein, includes conventional drilling muds, and equivalent drilling fluids of the slurry type, such as cement slurries.
Additional components are often added to drilling muds to impart desired characteristics, such as added weight or increased viscosity. These components may function physically, as in the case of barite, which is added to increase weight; or chemically, as in the case of sulfuric acid or hydrofluoric acid as a deflocculent. The more complex drilling muds can be very costly and their loss can mean a substantial increase in the cost of drilling a well.
The particle size in common drilling muds can be from about 0.5 to 30 microns, with a small percentage (perhaps as much as 5%) of the particles being as large as 100 microns. The balance of the particles above this range can be removed in process of preparation and in separation of the rock cuttings prior to recirculation of the mud. Because of the constant cleaning and removal of larger particles, the drilling mud can bridge only very small fissures (less than 0.002 in.) within the formations as the muds are normally used.
When the formation penetrated by the well bore has openings or fissures larger than about 0.001-0.002″, the ordinary drilling muds will flow into the openings and escape from the well bore into the formation. This loss of drilling mud may be slow or rapid depending upon the degree of porosity or the size of the fissures or fractures in the formation. In more severe cases the loss of fluid may result in a drop in the hydrostatic head to the point of hydraulic pressure equalization, which may fall thousands of feet below the surface.
In this instance, several conditions may occur which endanger the drilling operation and result in considerable economic loss. In normal circumstances, the column of drilling mud assists in supporting the wall of the well bore. Therefore, when a well bore is partially or completely emptied of drilling mud, the well bore walls are deprived of the hydraulic pressure head of the column of drilling circulation fluid extending downward from the surface, and consequently there will be hundreds or even thousands of feet of unsupported well wall that will be free to slough off and to cave into the well bore. That sloughing off or caving in may stick or freeze drill pipe that may be in the well bore or casing that may be therein and which is in the process of being installed and cemented. This condition is at times so severe that wells have been abandoned, or must be redrilled, because of it.
Additionally, the drilling mud is weighted to accommodate the depth of hole which has been drilled. This is done to minimize the danger of unequal pressures allowing a formation to release a bubble of gas, or a surge of oil or water toward the surface, causing a blowout of the well.
When drilling mud is lost in a well bore, the formation penetrated may be under great pressure which, if sufficient to overcome the static head of drilling mud remaining in the well bore, will cause a blowout, endangering the well, the financial investment in it, and the lives and safety of the personnel on site.
Where casing is being installed and cemented in place or cement plugs are being installed or other cementing operations are taking place, Portland cement slurries are often employed and these slurries likewise become lost through porous or fractured formations penetrated by the well bore.
As oil and gas wells are being drilled to progressively greater depths in the earth the problem of preventing or curing lost circulation becomes increasingly difficult largely due to the high differential in pressures encountered in the formations penetrated by deep well bores.
Where the well bore has penetrated depleted porous oil and gas formations and the pressures therein have become largely exhausted, the differential pressures may be 10,000 p.s.i. on the borehole side, forcing the drilling mud or cement slurries into the porous formations.
Lost circulation of drilling fluids has been a problem since the earliest days of well drilling. Many methods have been tried to solve the problem and many materials have been used as additives for preventing lost circulation.
There are a variety of lost circulation additives which are used. In particular, lost circulation additives can be flakes, fibers, and granular.
Drilling fluids are formulated to intentionally seal porous formations during drilling in order to stabilize the borehole and to control fluid loss. However, formations are frequently encountered that are so porous as to increase the loss of drilling fluids beyond an acceptable limit despite the use of lost circulation additives. Furthermore, a borehole may penetrate a fracture in the formation through which most of the drilling fluid may be lost.
In order to close off large pores and fractures that drain drilling fluid from the borehole, it is necessary to place the loss circulation material at the proper location and to be able to clean up the well bore after treatment is completed. The present invention offers a method for accomplishing this in a borehole whether the well is being drilled with aqueous drilling fluids, oil based drilling fluids or synthetic based drilling fluids.
A disadvantage with many previous loss circulation fluids and drilling fluids is that they contain a large amount of solids (e.g., barite, hematite or ilmenite) from the various components present, such as the weighting materials or other materials used to plug the lost circulation zones, such as ground nut shells, ground fibrous materials or ground plastics such as polyethylene.
Thus, there is a need to provide drilling fluids, completion fluids, and loss circulation fluids that can be preferably solids-free or have low solids content in the drilling fluid in order to avoid or minimize one or more of the above-mentioned disadvantages.
There is also a need to insulate the annular space of a producing wellbore, after drilling and completion operations are conducted, with a fluid that can retain the heat up the production string to minimize the deposition of waxes or the formation of hydrates, and the like.
It is often desirable that this annular space fluid or packer fluid acts to insulate the production fluid from cooling too rapidly. This acts to prevent the production fluid from waxing out and depositing on a colder and higher section of the production tubing as the producing oil or condensate hydrocarbon falls below its cloud point and waxes out.
By reducing the viscosity of an annular space or packer fluid by increasing the viscosity increasing components such as polymers, or preferably enabling cessation of viscosity flow as with a gel structure, the thermal convection is also being reduced and thermal conduction can increase thereby enhancing the insulating properties of the annular space.

Weighted zero solids loss circulation, fluid loss and insulating annular space fluid systems


An accessory frame for selectively coupling components to an optical microscope for imaging of a subject is provided. The optical microscope has a body including an undercarriage. The accessory frame includes a mounting plate that attaches to the undercarriage of the microscope. The mounting plate includes a first attachment port and a second attachment port. The first attachment port is configured to couple a first optical assembly in an optical path of the microscope between an objective lens of the microscope and the subject. The second attachment port is configured to couple a second optical assembly to the microscope body with at least a portion of the optical path of the second optical assembly being outside of the optical path of the microscope.

Surgical microscopes provide a magnified view of the operating field to the surgeon. Ophthalmic surgical microscopes are commonly stereo zoom microscopes with binocular view ports for the surgeon, and frequently have one or two observer view ports at ninety degrees (left and right) to the surgeon. The working distance between the objective lens of the microscope and the surface of a patient eye may range from about 100 mm to about 200 mm. At this working distance, which provides a suitable field of access for the manual work of the surgeon, the field of view within a patient eye may be quite limited. It is quite common to then use an intermediate lens, such as the Binocular Indirect Ophthalmo Microscope (BIOM) of Oculus Optikgerat, to modify the magnification and field of view for the surgeon. This intermediate lens is mounted to the under-carriage of the microscope head, and includes mechanics to adjust focus, and to flip the lens into and out of the field of view of the microscope.
Other illumination or imaging devices may also be used in the surgical field. Ideally, all illumination and imaging sources would be directly integrated coaxial to and within the optical path of the operating microscope, without impacting the operating field for the surgeon, the observers, the anesthesiologists, and the like. This is not always possible. Without full integration as such, it is still desirable to provide a readily maneuverable mount for imaging and other accessories that is closely coupled to the surgical field, and the mechanical controls and attributes that are already integral to a well-functioning operating microscope.
A particular case of interest is the incorporation of optical coherence tomography (OCT) imaging into the surgical visualization practice. OCT provides high resolution imaging of ocular tissue microstructure, and is showing great promise to provide information to the surgeon that will improve therapeutic outcomes, and reduce the total economic burdens of surgery by reducing risk and reducing re-work. The current generation of OCT, known generally as Fourier Domain OCT, provides very fast volumetric images (>30 mega-voxels per second) at very high resolution (2.0 μm to 6.0 μm axial resolution, 10.0 μm to 20 μm lateral resolution) particularly well suited to visualizing the fine tissue layers and membranes that are often the subject of the surgical effort. In contrast to microscope visualization, OCT provides depth-resolved images, highlighting subsurface physiology and pathology, with full volumes over a 30 to 70 degree field of view acquired in about 1 to 3 seconds. However, the alignment requirements of OCT, particularly for retina imaging, but also for cornea imaging, may be quite demanding to obtain high quality images. A flexible, finely controlled, and stable imaging platform is desirable.
At present, there are no commercially available operating microscopes with integrated OCT capabilities. The Assignee of the present application has demonstrated handheld OCT imaging as discussed in, for example, U.S. Patent Application Publication No. 2007/0081166 entitled PORTABLE OPTICAL COHERENCE TOMOGRAPHY (OCT) DEVICES AND RELATED SYSTEMS; U.S. Patent Application Publication No. 2009/0268020 entitled OPTICAL COHERENCE TOMOGRAPHY (OCT) IMAGING SYSTEMS FOR USE IN PEDIATRIC OPHTHALMIC APPLICATIONS AND RELATED METHODS AND COMPUTER PROGRAM PRODUCTS; and U.S. Patent Application Publication No. 2009/0141237 entitled INTEGRATED OPTICAL COHERENCE IMAGING SYSTEMS FOR USE IN OPHTHALMIC APPLICATIONS AND RELATED METHODS AND COMPUTER PROGRAM PRODUCTS. Devices discussed therein are finding increasing utility in the operative field. However, in some embodiments, the handheld device may be relatively difficult to align and stabilize for imaging in the operating field.
Approaches have been established to address the stabilization issue. For example, one approach to stabilize a handheld probe is to use a simple planar mount coupled to the objective lens of the microscope. This device has a fixed armature length, and coarsely rotates around the lens. There are no height adjustments, and there is no ballast to control torque on the microscope head. Another approach has been adopted by Optovue. This approach uses an articulating arm attached to a structure other than the operating microscope. This approach lacks the fine control afforded by a well engineered operating microscope, and risks being obstructive to the broader operating field. A third approach has been to use an independent boom mount, with balance similar to an operating microscope, as illustrated in, for example, U.S. Pat. No. 8,064,989. This approach may add unnecessary bulk to the limited space of the operating theater.

This patent is subject to a terminal disclaimer.

Imaging accessory frame for integration with an operating microscope


Single use or disposable cutting blocks and methods for utilizing same are disclosed. The blocks are preferably constructed of polymer and/or other suitable low cost and light weight materials. The blocks may be adapted for use with low friction cutting instruments, as well as other such cutting instruments. Several differently sized and configured blocks may be utilized to perform a single surgical procedure. In addition, kits housing one or more such blocks, with or without other instruments are possible.

The present invention relates to the field of orthopedic surgery, and in particular, to disposable resection guides and methods of utilizing same for use during total joint replacement surgery.
Many surgical operations call for the accurate and precise cuts of bone or bone material. Typically, these cuts, or resections, are made using surgical saws or milling devices. These instruments, while excellent at actually performing such cuts, often times require the use of external guides in surgical procedures calling for accurate cuts. For example, a surgeon performing a total knee arthroplasty must make several cuts in the distal end of the femur to properly fit a prosthetic femoral component thereon. The position of such cuts ultimately determines the positioning and stability of the femoral component. Thus, if such resections are incorrectly made, the surgery can result in failure and require further corrective procedures.
For this and other reasons, surgeons often employ the use of surgical cutting guides, known also as cutting blocks. These blocks typically include guiding surfaces which aid in guiding the cutting device during the cutting of the bone material. These guiding surfaces may simply be flat surfaces, or in certain cases, open slots which allow a cutting instrument to be inserted and guided therethrough. One specific type of cutting block is a block utilized during a total knee arthroplasty having four guiding surfaces utilized to create four cuts on an already at least partially resected distal portion of the femur. These guides are typically mounted on a prepared distal femoral surface, and the four cuts are generally referred to as anterior and posterior cuts, and anterior and posterior chamfer cuts. Examples of these femoral cutting blocks are shown in U.S. Pat. No. 5,454,816 to Ashby, U.S. Pat. No. 6,258,095 to Lombardo et al., U.S. Pat. No. 6,558,391 to Axelson, Jr. et al, and U.S. Pat. App. Pub. No. 2005/0228393 to Williams et al., the respective disclosures of which are hereby incorporated by reference herein.
While cutting blocks such as those described above are useful in performing the various cuts on a bone, they have their drawbacks. Most importantly, the manufacturing costs associated with such blocks are often quite high. A standard block is typically constructed of a suitable metallic material machined from a solid block or from several solid pieces of a suitable metallic material assembled together to provide a block with one or more guiding surfaces which allow for the various cuts to be accurately and precisely performed. These materials and the manufacture and manipulation of same are generally costly. Often times, these relatively high manufacturing costs, require the expensive cutting blocks to be utilized in multiple surgeries. This re-use often requires the cleaning and sterilization of such a block prior to each use, which necessarily adds an additional per-use cost.
Further to the high manufacturing and per-use costs of utilizing such well known cutting blocks, multiple uses of a single block may cause the guiding surfaces or the like of such blocks to become less accurate and precise. More particularly, multiple uses of such devices may allow for the greater chance of misaligning a cutting tool, such as a flat oscillating saw blade, due to wear of the cutting guide surfaces. In addition, even the most widely utilized sterilization procedures may not totally prevent the spread of dangerous bacteria or the like, which may in turn cause life threatening infections or other illnesses. Hence, a cheap, single use cutting block would be advantageous for use in common orthopedic procedures.
Therefore, there exists a need for a single use cutting block that can be inexpensively manufactured, while maintaining the required precise and accurate guiding surfaces needed for making cuts.


The machine (4) operates continuously and is a single unit having a prismatic construction and a body with an upper base that incorporates a large rotary platen (1), a number of workstations (5) that are placed in said platen and are provided with diametrically opposite curling and sealing compound lining devices (6) and (7), one or more sets of feeding (8) and discharge (9) devices and common actuation means for these stations (5), internal to the machine (4), which machine may operate with any lids (2) or bases of any profile, adapting to any shape of these by rotating the lids (2) in the workstations (5).

The earliest known antecedents for curlers of non-circular lids are those employing a press, with the disadvantage of the low production speed and the foreseeable imperfect finish resulting when the container is closed due to the need to allow exit of the lid core.
Later were implemented roller curlers, which generally used two complementary curling rollers with an incomplete finishing that resulted in a complicated closure of the container. These curling defects also cause a sealing compound fillet in a critical position, as the sealing compound wets the corners more than would be desirable.
Regarding sealing compound lining machines, tampon systems are known that use a sealing compound arc with a capacity on the order of 100 lids/min. that cannot provide sealing compound to the lid flange. Equally imperfect is sealing compound showering, also using a non-revolving method, in which a mask leaves open a projection of a multiplicity of small sealing compound droplets that together form a set of aligned points that replaces the sealing compound band, naturally also used for central application of sealing compound and not under the lid curl, although it is three times faster than the immediately preceding system.
Sealing compound lining machines with a discontinuous feed using belts with an indexed (start and stop) motion, with discontinuous lid feeding, have a seriously limited speed even in the only known case where the feed and discharge lines are duplicated as well as duplicating the feed of each one, and struggle to reach 400 lids/min.
In this unique machine a lid is deposited during the stop of the belt and another during its motion, with these lids being sent to corresponding sealing compound lining stations. In these stations and during the stops of the conveyor belt the lid rotates about its axis and the sealing compound, provided with servomechanisms that can only make it rotate about its vertical axis, applies the sealing compound in different angles of inclination resulting in a sealing compound lining band that does not maintain its distance from the lid edge, despite the cost of installing the electronic control servomechanisms for the guns; in addition, the type of lid to which the sealing compound lining is applied cannot be changed as it can only be positioned by gravity, the lids are not discharged with accurate regularity, and the machine cannot operate with any conventional drying oven, nor with two independent ovens or with an oven having two scoop towers.
As regards the lid-feeding device, in the cases described heretofore, with the exception of the aforementioned double feeding system, this is performed with the belt or the rotary base stopped, and under gravity.
One known system involves a lid held in a lower, displaceable base provided with an orifice to allow the lid to fall, together with jack-knife clips that hold the pile of remaining lids placed on top of the lowermost one, until the platform returns and the clips let the lids fall on the un-perforated area of said platform.
Another better-known system is the worm gear, with generally two opposite ones used that feed each lid to a lower platen provided with satellite platens in charge of feeding the lid tangentially and with the lid support stopped.
Finally, regarding discharge devices for curing or sealing compound lining machines, the initial system involved parallel tilt bars that guided the lid and released it after raising it.
This has subsequently been changed by a faster but less efficient system that is effected in an unsynchronised manner, as the lid slides when there is dust on the belt or due to the natural asynchrony from constant use or machine vibrations.
The applicant is not aware of any curling-sealing compound lining machine for non-circular container lids that has the simplicity, speed and is as free of errors and failures in the handling of lids as the one described hereunder.

Curling-sealing compound lining machine for non-circular metal lids of containers


Derivatives of 1,2-benzisoxazole-3-methanesulfonic acid, which are non-hygroscopic and non-hydrated and their use as intermediates from the preparation of zonisamide are disclosed. Further disclosed are processes of preparing zonisamide from these 1,2-benzisoxazole-3-methanesulfonic acid derivatives, processes of preparing exemplary 1,2-benzisoxazole-3-methanesulfonic acid derivatives and crystalline forms of exemplary 2-benzisoxazole-3-methanesulfonic acid derivatives. A novel process of preparing zonisamide is also disclosed.

3-(sulfamoylmethyl)-1,2-benzisoxazole, also named 1,2-benzisoxazole-3-methanesulfonamide and known as zonisamide is an active pharmaceutically agent that exhibits anti-convulsive and anti-neurotoxic activity and is therefore used as an anti-epileptic agent. Zonisamide has the following chemical formula:

A process of preparing zonisamide was first described in U.S. Pat. No. 4,172,896, to Uno H. et. al. (Dainippon Pharmaceutical Co.). The process taught in this patent is illustrated in Scheme 1 below and is effected by brominating benzioxazole acetic acid (also referred to herein as BIOA) to thereby provide 3-bromomethyl-1,2-benzisoxazole (Compound I); reacting 3-bromomethyl-1,2-benzisoxazole with sodium sulfite in a methanol-water mixture at 50° C., so as to obtain sodium 1,2-benzisoxazole-3-methanesulfonate (Compound II), which is also referred to hereinafter as BIOS-Na; reacting the thus obtained BIOS-Na with a large excess of phosphorus oxychloride so as to obtain 1,2-benzisoxazole-3-methanesulfonyl chloride (Compound III), which is also referred to hereinafter as BIOS-Cl); and reacting the thus obtained BIOS-Cl with gaseous ammonia in ethyl acetate to thereby obtain the zonisamide. The zonisamide is then recrystallized from ethyl acetate.

As is demonstrated in the Examples section that follows, while practicing the process taught in U.S. Pat. No. 4,172,896, it was found that the crude intermediate BIOS-Na is obtained by this process as a monohydrate (see, Reference Example 1). While such a hydrated intermediate reacts with the chlorinated agent (e.g., phosphorous oxychloride), the presence of water leads to the formation of hydrogen chloride. Furthermore, since the chlorinating agent reacts with the water, a large access thereof should be used in order to compensate for the loss of reagent that reacts with water. Since both hydrogen chloride and phosphorous oxychloride are considered hazardous, their presence in the reaction waste poses severe environmental problems.
In order to circumvent these limitations, the BIOS-Na monohydrate intermediate must be dried before the chlorination reaction. However, drying BIOS-Na monohydrate in an oven requires a prolonged time period of about 48 hours, whereby the resulting dried BIOS-Na is hygroscopic and thus is difficult to handle and store.
Another process of preparing zonisamide also involves the preparation of BIOS-Na. In this process, BIOS-Na is formed by sulfonating BIOA, with chlorosulfonic acid, to thereby obtain benzioxazole sulfonic acid (also referred to herein as BIOS-H), which is then transformed to BIOS-Na using NaOH. However, such a sulfonation reaction is non-selective and results in a substantial amount of the disulfonated benzioxazole derivative.
WO 03/020708 (by Teva Pharmaceutical Industries Ltd.) teaches various intermediates of zonisamide, processes for their preparation and zonisamide prepared therefrom. Particularly, this patent application teaches the preparation of the sulfonic acid intermediate derivative, BIOS-H, by reacting BIOA with acetic anhydride and sulfuric acid. The BIOS-H is thereafter converted to BIOS-Na. According to the teachings of WO 03/020708, using such a process avoids the formation of the dislufonated product and further avoids the use of chlorosulfonic acid, thus being more environmentally friendly. The preparation of BIOS-Na from BIOA via BIOS-H using the process taught in WO 03/030708 is illustrated in Scheme 2 below.

Further according to the teachings of this patent, the preparation of various metallic salts (e.g., sodium, calcium and barium) of BIOS-H is described. These salts are mostly obtained in a hydrated crystalline form thereof, containing between about 1.5 and about 7 weight percentages of water. As is discussed hereinabove, the presence of water in the zonisamide intermediate obtained prior to chlorination, is highly disadvantageous since it requires the use of excess chlorinated agent and involves the production of hydrogen chloride.
WO 03/072552 (to Teva Pharmaceuticals USA, Inc.) describes a process of preparing zonisamide via the intermediate BIOS-Cl. According to the teachings of this patent application, BIOS-Cl is prepared by chlorinating 1,2-benzisoxazole-3-methanesulfonic acid (BIOS-H) or BIOS-Na with thionyl chloride (SOCl2) in an organic solvent. The BIOS-Cl is then reacted with ammonia to thereby obtain zonisamide.
The synthesis of zonisamide from BIOS-H or BIOS-Na via BIOS-Cl, as taught in WO 03/072552 is illustrated in Scheme 3 below.

Thus, the processes taught in the art for preparing BIOS-Na as an intermediate in the synthesis of zonisamide and related compound are limited by the formation of hydrated forms thereof, which either complicates the process as the presence of water requires using a molar excess of the chlorinating agents and involves formation of hydrochloric acid or requires a laborious drying process, whereby the obtained dry intermediate is highly hygroscopic.
In addition, in all of the presently known processes of preparing zonisamide, chlorinating agents such as phosphorus oxychloride, thionyl chloride and phosphorus pentachloride, being some of the most readily available chlorinating agents around the world, are utilized. These chlorinating agents are considered hazardous and in some countries, shipping into and/or ground transportation thereof is restricted. An alternative process of preparing zonisamide, which circumvents the need to use such environmentally unfriendly reagents has not been suggested nor practiced hitherto.
There is thus a widely recognized need for and it would be highly advantageous to have a novel process of preparing zonisamide and particularly a novel process of preparing intermediates thereof, devoid of the above limitations.

Derivatives of 1,2-benzisoxazole-3-methane sulfonic acid as novel intermediates for the synthesis of zonisamide