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Vacuum cleaner and device having ion generator |
When the electrically driven fan (14) of a vacuum cleaner is driven, air containing dust is drawn into the cleaner main body (1) through a hose (7) connected to a hose socket (8) and is exhausted into the outside of the cleaner main body (1) through an exhaust port (1b) via first and second suction passageways (10, 13). Disposed outside the first suction passageway (10) is an ion generator (23), it being arranged that plus and minus ions generated in the ion generator (23) are fed to the air stream flowing in the first suction passageway (10). Since the plus and minus ions kill floating germs in the air stream, the exhaust can be purified. |
1. An electric vacuum cleaner that, while driving an electric blower, sucks in air containing dust, then passes the airthrough a suction air passage, and then discharges the air out of the electric vacuum cleaner, comprising: an ion generator for generating H+(H2O)n as positive ions and O2−(H2O)m as negative ions, wherein airborne germs present in air are killed by the positive and negative ions. 2. The electric vacuum cleaner according to claim 1, wherein ions generated by the ion generator are fed into the suction air passage. 3. (Canceled) 4. The electric vacuum cleaner according to claim 2, wherein the ion generator is disposed away from a heat source inside a body of the electric vacuum cleaner. 5. An electric vacuum cleaner that, while driving an electric blower, sucks in air and then discharges the air out of the electric vacuum cleaner, comprising: an ion generator for generating H+(H2O)n as positive ions and O2−(H2O)m as negative ions, wherein the air is discharged out of the electric vacuum cleaner after being mixed with the positive and negative ions so that airborne germs present in air are killed by the positive and negative ions. 6. The electric vacuum cleaner according to claim 5, wherein the air sucked into the electric vacuum cleaner is discharged out of the electric vacuum cleaner after being passed through a purification filter, and the air is mixed with the ions after being passed through the purification filter. 7-12. (Canceled) 13. The device according to claim 6, wherein, when air is fed to an ion generating part of the ion generator at a rate of 50 cm/s or more, concentrations of the positive and negative ions are each 10,000 ions/cm3 or more at a position 10 cm away from the ion generating part. 14. An electric vacuum cleaner that has casters arranged on both side faces of a body having an electric blower housed therein and that exhausts the electric blower of air through ventilation openings formed in the casters, comprising: an ion generator that generates H+(H2O)n as positive ions and O2−(H2O)m as negative ions into a mixing chamber formed by the casters wherein airborne germs present in air are killed by the positive and negative ions generated by the ion generator. 15. An electric vacuum cleaner that has an electric blower and an ion generator housed in a body, the body comprising: a drive switch for driving the ion generator, the drive switch being provided independently of a control panel for controlling the electric vacuum cleaner, wherein airborne germs present in air are killed by the ion generator. 16. The electric vacuum cleaner according to claim 15, further comprising: timer means for driving the electric blower and the ion generator for a predetermined length of time after the drive switch is operated. 17. The electric vacuum cleaner according to claim 1, wherein quantities of ions generated by the ion generator is controlled according to a power with which the electric blower is driven. 18. The electric vacuum cleaner according to claim 1, wherein the ion generator is driven for a predetermined length of time according to a storage state of the electric vacuum cleaner. 19. The electric vacuum cleaner according to claim 1, wherein the ion generator has two ion generating electrodes so that the positive and negative ions are generated from the two separate electrodes. 20. The electric vacuum cleaner according to claim 1, wherein the ion generator can variably control a proportion between quantities of positive and negative ions generated. |
<SOH> BACKGROUND ART <EOH>As a conventional electric vacuum cleaner provided with an ozone generating function, the one disclosed in Japanese Patent Application Laid-Open No. H1-238815 will be described below with reference to FIG. 30 . In this conventional electric vacuum cleaner, inside a body 101 thereof is formed a suction air passage 104 that runs from a hose socket 102 formed in the front wall of the body 101 to an exhaust opening 103 formed in the rear wall of the body 101 , and in this suction air passage 104 are arranged a dust collection bag 105 , a dust filter 106 , and an electric blower 107 in this order. The dust collection bag 105 permits air to pass therethrough. The electric blower 107 communicates with the exhaust opening 103 . When the electric blower 107 is driven, air containing dust is sucked in through a suction hose 108 fitted into the hose socket 102 , is then passed through the dust collection bag 105 , dust filter 106 , and electric blower 107 , and is then discharged out of the body 101 through the exhaust opening 103 . Meanwhile, the dust collection bag 105 removes the dust contained in the air. On the other hand, inside the body 101 of this electric vacuum cleaner, outside and above the suction air passage 104 is formed an ozone reservoir 109 , in which an ozone generator 110 is provided. While the electric blower 107 is operating, ozone generated by the ozone generator 110 is reserved in the ozone reservoir 109 , and, when the electric blower 107 is de-energized, valves 111 and 112 are opened so that the reserved ozone is fed into the suction air passage 104 so as to kill germs present in the suction air passage 104 . In this conventional electric vacuum cleaner, the ozone fed into the suction air passage 104 acts on the stream of air that has been cleaned by the dust collection bag 105 , but does not sufficiently act on the dust and germs collected in the dust collection bag 105 . This makes it impossible for ozone to exert a satisfactory antibacterial effect. Moreover, since ozone is reserved in the ozone reservoir 109 during operation, the body 101 , which is formed of synthetic resin, is exposed to the reserved ozone for a long time. This causes the body 101 to deteriorate, making it prone to cracks and breakage in the relevant part thereof In particular, in a vacuum-type cleaner, cracks are likely to develop in a part thereof where the pressure is low during operation, lowering the suction performance and leading ultimately to a burst. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is an external side view showing the electric vacuum cleaner of a first embodiment of the invention. FIG. 2 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner. FIG. 3 is an enlarged side sectional view showing the internal construction of the ion generator used in the electric vacuum cleaner. FIG. 4 is an enlarged view of another example of the needle-shaped electrode of the ion generator. FIG. 5 is an enlarged view of still another example of the needle-shaped electrode of the ion generator. FIG. 6 is a sie sectional view showing the internal construction of the electric vacuum cleaner of a second embodiment of the invention. FIG. 7 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a third embodiment of the invention. FIG. 8 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a fourth embodiment of the invention. FIG. 9 is an external perspective view of the ion generator used in the electric vacuum cleaner, as seen from the ion generating element side. FIG. 10 is an external perspective view of the ion generator, as seen from the side opposite to the ion generating element. FIG. 11 is an exploded perspective view of the ion generator. FIG. 12A is an outline perspective view showing the ion generating element of the ion generator. FIG. 12B is a sectional view showing the ion generating element of the ion generator. FIG. 13 is an enlarged side sectional view sowing another example of the infernal construction of the ion generator. FIG. 14 is a side sectional view around the exhaust opening, showing the internal construction of the body of another embodiment of the electric vacuum cleaner. FIG. 15 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a fifth embodiment of the invention. FIG. 16 is a side sectional view around the exhaust opening, showing the internal construction of the body of another embodiment of the electric vacuum cleaner. FIG. 17 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a sixth embodiment of the invention. FIG. 18 is a vertical sectional view showing the internal construction of the body, in its rear part, of the electric vacuum cleaner of a sixth embodiment of the invention. FIG. 19 is a sectional view taken along line A-A shown in FIG. 18 . FIG. 20A is a side view showing the posture of the body of the electric vacuum cleaner during cleaning operation. FIG. 20B is a side view showing the posture of the body of the electric vacuum cleaner during storage. FIG. 21 is a sectional view taken along line A-A shown in FIG. 18 , showing another example of the electric vacuum cleaner. FIG. 22 is a vertical sectional view showing the internal construction of the body, in its rear part, of still another example of the electric vacuum cleaner. FIG. 23 is an external perspective view showing the electric vacuum cleaner of an eighth embodiment of the invention. FIG. 24 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner. FIG. 25 is a side sectional view showing the internal construction of the body of the electric vacuum cleaner of a ninth embodiment of the invention. FIG. 26 is a diagram showing the measurements of the concentrations of ions generated by the electric vacuum cleaner. FIG. 27 is a diagram showing the effect of eliminating ammonia achieved by the operation of the electric vacuum cleaner. FIG. 28 is a side sectional view showing the internal construction of the body of an example of an exhaust-recycling-type electric vacuum cleaner provided with an ion generator. FIG. 29A is a circuit diagram of the control circuit for controlling the electric blower and ion generator in an electric vacuum cleaner according to the invention, showing an example of the control circuit that drives the electric blower and ion generator simultaneously. FIG. 29B is a circuit diagram of the control circuit for controlling the electric blower and ion generator in an electric vacuum cleaner according to the invention, showing an example of the control circuit used when the ion generator shown in FIG. 13 is provided in the body. FIG. 30 is an external side sectional view of a conventional electric vacuum cleaner. detailed-description description="Detailed Description" end="lead"? |
Wiping device for wiping surfaces to be cleaned |
The invention relates to a wiping device for wiping surfaces to be cleaned, especially floor surfaces, comprising a plate-type or frame-type wiping element holder (1), preferably in an essentially long, rectangular form, and a wiping element (4) consisting of textile material or the like, which is adapted and fixed to the wiping element holder (1). Said wiping element (4) respectively comprises, on the upper side facing the wiping element holder (1), close to the two opposing sides, and close to the narrow sides in the long, rectangular form, a narrow fixing strip (5), which is applied with its ends to the wiping element (5) [sic]. Said fixing strip extends approximately transversally on the wiping element holder (1) when the wiping element (4) is fixed to the same (1). Position fixing arrangements are provided on the wiping element holder (1), where the fixing strips (5) should extend when the wiping element is fixed (4). The fixing strips (5) especially consist of textile material or the like and are sewn at the ends thereof to the wiping element (4). The position fixing arrangements (7) are especially embodied as edge recesses starting from the ends, in which the fixing strips (5) are placed in the correct position. |
1. Wiping device for wiping surfaces that are to be cleaned, in particular floor surfaces, comprising a plate-type or frame-type wiping element holder (1), preferably of substantially longitudinal extending rectangular shape, and a wiping element (4) of textile or textile-like material matching the wiping element holder (1) and secured to the said wiping element holder (1), wherein the wiping element (4) has on the upper side facing the wiping element holder (1) adjacent to two opposite sides, and in the case of a longitudinally extending rectangular shape, close to the narrow sides, in each case a fixing element for securing the wiping element (4) to the wiping element holder (1), the said element running approximately crosswise over the wiping element holder (1) when the wiping element (4) is secured in position, characterized in that the fixing elements on the upper side of the wiping element (4) are designed as narrow fixing strips (5) attached only at their ends to the wiping element (4), and that position fixing arrangements (7) are provided on the wiping element holder (1) where the fixing strips (5) are to run when the wiping element (4) is fixed in position, the said means preventing an undesirable longitudinal displacement of the wiping element (4) relative to the wiping element holder (1). 2. Wiping device according to claim 1, characterized in that the fixing strips (5) consist of textile or textile-like material. 3. Wiping device according to claim 2, characterized in that the fixing strips (5) consist of the same material as the basic fabric of the wiping element (4). 4. Wiping device according to claim 2, characterized in that the textile or textile-like material is a synthetic fiber material or a synthetic fiber/natural fiber mixed material. 5. Wiping device according to claim 1, characterized in that the fixing strips (5) are attached to the wiping element (4) by stitching. 6. Wiping device according to claim 1, characterized in that the fixing strips (5) are attached to the wiping element (4) by welding. 7. Wiping device according to claim 1, characterized in that the fixing strips (5) are practically not elastically stretchable in their longitudinal direction. 8. Wiping device according to claim 1, characterized in that the fixing strips (5) are designed so that they stand apart from the upper side of the wiping element (4) even when the said wiping element (4) is not secured to the wiping element holder (1). 9. Wiping device according to claim 1, characterized in that for the formation of the position fixing arrangements (7), the wiping element holder (1) is designed to be trapezoidally tapering at the ends associated with the fixing strips (5) and the desired position of the fixing strips (5) lies in the trapezoidally tapering region. 10. Wiping device according to claim 1, characterized in that the position fixing arrangements (7) of the wiping element holder (1) are edge recesses in the wiping element holder (1) starting from the ends associated with the fixing strips (5), in which recesses the fixing strips (5) lie in the desired position. 11. Wiping device according to claim 1, characterized in that the position fixing arrangements (7) of the wiping element holder (1) are edge recesses arranged on the longitudinal sides of the wiping element holder (1) running approximately transversely to the fixing strips (5), in which recesses the fixing strips (5) lie in the desired position. 12. Wiping device according to claim 10, characterized in that the edge recesses are connected by a recess running on the upper side of the wiping element holder (1). 13. Wiping device according to claim 1, characterized in that the position fixing arrangements (7) of the wiping element holder (1) are edge projections arranged on the longitudinal sides of the wiping element holder (1) running approximately transversely to the fixing strips (5), which projections prevent a further slipping of the fixing strips (5) onto the wiping element holder (1). 14. Wiping device according to claim 1, characterized in that the position fixing arrangements (7) of the wiping element holder (1) are projections arranged on the upper side of the wiping element holder (1) that prevent a further slipping of the fixing strips (5) onto the wiping element holder (1). 15. Wiping device according to claim 1, characterized in that the wiping element holder (1) has a fixed plate and/or wire frame. 16. Wiping device according to claim 1, characterized in that the wiping element holder (1) has a foldable plate and/or wire frame. 17. Plate-type or frame-type wiping element holder (1) for a wiping device for wiping surfaces that are to be cleaned, in particular floor surfaces, in particular for a wiping device according to claim 1, characterized in that position fixing arrangements (7) are provided on the wiping element holder (1) at those places where fixing strips (5) of the wiping element (4) are to run when the wiping element (4) is secured to the wiping element holder (1). 18. (canceled) 19. Wiping element for a wiping device for wiping surfaces to be cleaned, in particular floor surfaces, that has a plate-type or frame-type wiping element holder (1), the wiping element (4) consisting of textile or textile-like material, wherein the wiping element (4) has on the upper side facing the wiping element holder (1) close to two sides lying opposite one another, in the case of a longitudinally extending rectangular shape close to the narrow sides, in each case a fixing element for securing the wiping element (4) to the wiping element holder (1), which element runs approximately transversely over the wiping element holder (1) when the wiping element (4) is secured in position, in particular for a wiping device according to claim 1, characterized in that the fixing elements on the upper side are designed as narrow fixing strips (5) attached only at their ends to the wiping element (4). 20. (canceled) 21. Wiping device according to claim 1, characterized in that the wiping element (4) is reversible and that the fixing strips (5) are attached to the edges of the wiping element (4) such that, in both positions of the wiping element (4), the fixing strips have essentially the same relative position to the wiping element (4). 22. Wiping device according to claim 21, characterized in that the wiping element (4) consists of two active cleaning layers (4a, 4b) that are firmly joined together, in particular are stitched together. 23. Wiping device according to claim 22, characterized in that the layers (4a, 4b) have different structures and/or surfaces and/or materials or material compositions. 24. Wiping device according to claim 22, characterized in that the fixing strips (5) are attached at the end sides between the layers (4a, 4b), in particular are stitched together with the layers (4a, 4b). 25. Wiping device according to claim 1, characterized in that the wiping element holder (1) has a hollow chamber for receiving a larger volume of cleaning fluid, which can flow onto the wiping element (4) fastened to the wiping element holder (1) via at least one outlet in the wiping element holder (1), or is formed by such a hollow chamber, and that the position fixing arrangements (7) are arranged on the hollow chamber (1) in an appropriate manner, the fixing strips (5) preferably being elastically extendible in their longitudinal direction. 26. Wiping element holder (1) for a wiping device according to claim 25, characterized in that position fixing arrangements (7) are provided on the wiping element holder (1) at the place where the fixing strips (5) are to run when the wiping element (4) is attached. |
Data recording/reproduction device and data recording/reproduction method |
In order to reproduce data in a stable manner by correction of random and burst errors of a wide range without lowering a transfer speed, C2 error correction for correcting an inter-sector error is carried out in addition to the conventional C1 error correction for correcting an error generated in a sector. The configuration of an error correction unit (or an ECC block) including C1 and C2 codes is formed as a track. That is to say, one track is used as the base of an ECC block unit. In this way, two ECC block units never exist in the same track. |
1. A data-recording/reproduction apparatus for recording data onto a disk-shaped recording medium including concentric recording tracks, each track divided into sectors by splitting said data into predetermined quantities to be recorded onto one of said sectors, each sector used as a minimum access unit, and for reproducing said data from said disk-shaped recording medium, said data-recording/reproduction apparatus comprising: recording/reproduction means for recording and reproducing data onto and from said disk-shaped recording medium; transport means for transporting said recording/reproduction means to a predetermined one of said recording tracks on said disk-shaped recording medium; access control means for executing control to access data of an amount equivalent to one recording track by starting said access from a one of said sectors existing in said predetermined recording track as a first sector accessible to said recording/reproduction means transported to said predetermined recording track; first error-correction-code generation means for generating a first error correction code for correcting an error generated in a first predetermined data amount unit of said accessed data of an amount equivalent to one recording track; and second error-correction-code generation means for generating a second error correction code for correcting an error generated in a plurality of said first predetermined data amount units, wherein only one error correction code block including said generated first error correction code and said generated second error correction code is generated for each of said recording tracks. 2. The data-recording/reproduction apparatus according to claim 1, said data-recording/reproduction apparatus further comprising: first error correction means for correcting an error generated in said first predetermined data amount unit of said accessed data of an amount equivalent to one recording track based on said first error correction code; and second error correction means for correcting an error generated in a plurality of said first predetermined data amount units based on said second error correction code. 3. The data-recording/reproduction apparatus according to claim 1 wherein, at a time to write data onto said disk-shaped recording medium, said access control means sequentially assigns relative-position addresses to said sectors on said predetermined recording track in an order starting with a one of said sectors that becomes writable first in said predetermined recording track. 4. The data-recording/reproduction apparatus according to claim 1 wherein, at a time to read out pieces of data from said disk-shaped recording medium, said recording/reproduction means is transported to said predetermined recording track and said access control means sequentially reads out each of said pieces of data from one of said sectors in said predetermined recording track in an order starting with a one of said sectors that becomes readable first in said predetermined recording track and relocates said pieces of data based on information on relative positions each assigned to one of said sectors. 5. The data-recording/reproduction apparatus according to claim 4, said data-recording/reproduction apparatus further comprising storage means for storing said pieces of data read out from said disk-shaped recording medium, wherein control is executed to store said pieces of data read out from said disk-shaped recording medium at predetermined locations in said storage means based on said information on relative positions. 6. The data-recording/reproduction apparatus according to claim 4, said data-recording/reproduction apparatus further comprising storage means for storing said pieces of data read out from said disk-shaped recording medium, wherein control is executed so that, after said pieces of data for one track have been stored in said storage means, said pieces of data are read out from said storage means based on said information on relative positions. 7. The data-recording/reproduction apparatus according to claim 4, said data-recording/reproduction apparatus further comprising storage means for storing said pieces of data read out from said disk-shaped recording medium, wherein: said pieces of data read out from said predetermined recording track are stored in said storage means sequentially; as one of said pieces of data is read out from one of said sectors included in said predetermined recording track as a sector determined to be a first sector based on said information on relative positions, said pieces of data read out from said first sector and said sectors following said first sector are output; and then, said pieces of data already stored in said storage means are output. 8. The data-recording/reproduction apparatus according to claim 1, wherein said second error-correction-code generation means generates a second error correction code by using a Reed-Solomon encode method. 9. The data-recording/reproduction apparatus according to claim 1, wherein said disk-shaped recording medium conforms to a Zone Bit Recording method in which a number of sectors included in each of said recording tracks is varied in dependence on a location of said recording track in a radial direction of said disk-shaped recording medium. 9A. (Cancelled) 10. The data-recording/reproduction apparatus according to claim 18, wherein said error correction block configuration is changed by changing one of a configuration of the unit of said second error correction code and a configuration of the unit of said first error correction code. 11. The data-recording/reproduction apparatus according to claim 1, wherein an interleave structure is adopted as one of the unit of said second error correction code and the unit of said first error correction code. 12. The data-recording/reproduction apparatus according to claim 2, further comprising selection means, wherein an error is corrected by using one of: both said first error correction means and said second error correction means; only said first error correction means; and only said second error correction means. 13. The data-recording/reproduction apparatus according to claim 1, wherein said data to be recorded on said disk-shaped recording medium includes at least a piece of data for which only said first error correction code is generated by said first error-correction-code generation means. 14. A data-recording/reproduction method for recording data onto a disk-shaped recording medium having concentric recording tracks each divided into sectors by splitting said data into predetermined quantities, each to be recorded onto one of said sectors, and each used as a minimum access unit, and for reproducing said data from said disk-shaped recording medium, said data-recording/reproduction method comprising the steps of: recording and reproducing data onto and from said disk-shaped recording medium to and from a predetermined one of said recording tracks on said disk-shaped recording medium; executing control to access data of an amount equivalent to one recording track by starting said access from a one of said sectors existing in said predetermined recording track as a first sector accessible to said recording/reproduction means transported to said predetermined recording track; generating only one error correction block including a first error correction code and a second error correction code for each of said recording tracks in an operation recording data to said disk-shaped recording medium, said first error correction code correcting an error generated in a first predetermined data amount unit of said accessed data of an amount equivalent to one recording track, said second error correction code correcting an error generated in a plurality of said first predetermined data amount units. 15. The data-recording/reproduction method according to claim 14, wherein in an operation to reproduce data from said disk-shaped recording medium errors are corrected based on said first error correction code and other errors are corrected based on said second error correction code. 16. A data-recording/reproduction apparatus comprising: access control means for executing control to access data of an amount equivalent to one recording track by starting said access from a one of a plurality of sectors existing in a predetermined recording track as a first sector accessible to a recording/reproduction means transported to said predetermined recording track; first error-correction-code generation means for generating a first error correction code for correcting an error generated in a first predetermined data amount unit of said accessed data of an amount equivalent to one recording track; and second error-correction-code generation means for generating a second error correction code for correcting an error generated in a plurality of said first predetermined data amount units, wherein only one error correction code block including said generated first error correction code and said generated second error correction code is generated for each recording track. 17. A data-recording/reproduction apparatus for recording data onto a disk-shaped recording medium comprising concentric recording tracks, each divided into sectors by splitting said data into predetermined quantities, each to be recorded onto one of said sectors, and each used as a minimum access unit, and for reproducing said data from said disk-shaped recording medium, said data-recording/reproduction apparatus comprising: recording/reproduction means for recording and reproducing data onto and from said disk-shaped recording medium; transport means for transporting said recording/reproduction means to a predetermined one of said recording tracks on said disk-shaped recording medium; access control means for executing control of sequentially assigning relative-position addresses to said sectors on said predetermined recording track in an order starting with a one of said sectors that becomes first accessible to said recording/reproduction means transported to said predetermined recording track and writing data of an amount equivalent to one recording track, and for reading out data of an amount equivalent to one recording track from said sectors on said predetermined recording track starting from the one of said sectors that becomes first accessible to said recording/reproduction means transported to said predetermined recording track at a time of reproducing said data from said disk-shaped recording medium; and error-correction-code generation means for generating predetermined error correction codes to be included in data recorded at a time to write said data onto said disk-shaped recording medium along with said relative-position addresses. 18. the data-recording/reproductive apparatus according to claim 1, wherein said second error-correction-code generation means adopts an error correction block configuration changing from zone to zone on said disk-shaped recording medium. |
<SOH> BACKGROUND ART <EOH>With development of information technologies such as information processing and information communications, it becomes necessary to reutilize information created and edited in the past. For this reason, the information storage technology becomes important more and more. So far, information-recording apparatus using various kinds of media have been developed and become popular. The media used in the information-recording apparatus includes a magnetic tape and a magnetic disk. An example of the magnetic disk is a disk embedded in an HDD (Hard Disk Drive) used as an auxiliary storage apparatus adopting a magnetic recording method. A drive unit accommodates several pieces of magnetic media, which each serve as a recording medium. A spindle motor rotates the pieces of recording media at high speed. Each piece of magnetic media is coated with a magnetic substance plated with a material such as nickel or phosphor. A magnetic head scans the face of the rotating media in the radial direction to write data onto the media by generating magnetization corresponding to the data on the face of the media, or to read out data from the media. The hard disk has already become generally and widely popular. For example, the hard disk is employed in a personal computer as a standard external storage device in which various kinds of software are installed and created as well as edited files are stored. The software installed in the hard disk includes an operating system (OS) for starting up the computer and application programs. Usually, the hard disk drive employing the hard disk is connected to the main unit of the personal computer through a standard interface such as an IDE (Integrated Drive Electronics) interface or an SCSI (Small Computer System Interface). A file system manages storage areas of the hard disk. The file system is a sub-system of the operating system. The file system includes a FAT (File Allocation Table). Recently, efforts to increase the storage capacity of the hard disk are in progress. Accompanying the progress of the efforts to increase the storage capacity of the hard disk, the application field of the hard disk is widened to include apparatus such as a hard-disk recorder for storing AV (audio and visual) contents received from a broadcasting station, and the use of the hard disk as a storage unit for storing contents as well as the conventional use thereof as an auxiliary storage apparatus of a computer is started. By taking a case of using the hard disk as an auxiliary storage apparatus of a computer as an example, the following description considers a method of physically formatting the hard disk and an operation to write data onto the hard disk. As partitions for recording data onto the hard disk, a number of concentric tracks are formed on the hard disk. Increasing sequence numbers 0 , 1 and so on are assigned to the tracks starting with the track on the outermost circumference as track numbers in a direction toward the track on the innermost circumference. The larger the number of tracks created on the surface of the hard disk, the larger the storage capacity of the hard disk serving as recording media. In addition, each of the tracks is divided into sectors each used as a recording unit. Normal operations to read out and write data from and onto the hard disk are carried out in sector units. The size of the sector varies from media to media. However, the size of the sector of a hard disk is generally set at a fixed value of 512 bytes. In addition, in order to make the recording density uniform for all the tracks by taking the efficiency of the utilization of the media into consideration, each of the tracks is divided into such a number of sectors that, the farther the location of a track from the center of the hard disk, the larger the number of sectors included in the track. This is because, the larger the radius of a circumference on which a track is created on the hard disk, the longer the circumference and, hence, the longer the track. The technique to provide each of the tracks with sectors in this way is referred to as a ‘Zone Bit Recording’ method. In addition, in the case of an HDD with a configuration in which several pieces of media overlap with each other with their centers aligned along a straight line, tracks each created on one of the pieces of media as tracks having the same track number can be considered as tracks forming the wall of a cylinder. As a matter of fact, such tracks are referred to as a cylinder. The same track number assigned to tracks forming a cylinder is used as a cylinder number assigned to the cylinder. Much like the track numbers, cylinder numbers are increasing sequence numbers 0 , 1 and so on, which are assigned to cylinders starting with the cylinder on the outermost circumference of the HDD in a direction toward a cylinder on the innermost circumference. A plurality of heads each inserted into a gap between 2 adjacent pieces of media always moves from one cylinder to another as a single assembly. A CHS mode can be given as a kind of addressing, which is a method of specifying a target sector. The CHS mode is a method of making an access to desired data by specifying the PBA (Physical Block Address) of a location on a disk-like piece of recording media as the PBA of the location of the target sector in a format including parameters arranged in a C (Cylinder), H (Head) and S (sector) sequence. With the CHS method, on the other hand, there is a limit on CHS parameters that can be specified in the main unit of a computer serving as the host of the HDD, and the limit does not allow the addressing to keep up with the rising storage capacity of the hard disk. In order to solve this problem, an LBA (Logical Block Address) mode is adopted. An LBA is expressed as logical sequence numbers including a cylinder number, a head number and a sector number, which each start from 0. In the conventional HDD, in order to read out data from recording media by making an access to the media, first of all, the magnetic head is moved over the recording media in a seek operation to a track having a target sector containing the data. Then, the magnetic head waits for the desired sector on the rotating recording media to arrive at a position right under the magnetic head. This state of waiting for the desired sector on the rotating recording media to arrive at a position right under the magnetic head is referred to as a rotation wait. In general, the storage capacity of the disk can be increased as the track density raises and the track density can be raised as the width of the track decreases. Thus, in order to write and read out data into and from a track with a high degree of accuracy, high precision of the positioning of the magnetic head is required. In order to meet this requirement, there is adopted a servo technique for always adjusting the position of the magnetic head to the center of a track containing the target sector. The servo technique is based on signals recorded on each track at fixed intervals. These signals are referred to as a servo pattern. By reading out this servo pattern from a track through use of the magnetic head, it is possible to check whether or not the magnetic head is positioned at the center of the track. The servo pattern is embedded on each track with a high degree of precision in advance when the HDD is made in a manufacturing process. A servo area is used for recording the signals for positioning the magnetic head and information such as a cylinder number, a head number and a servo number. A number of conventional HDDs adopt an interface such as the IDE or SCSI interface intended for connecting an HDD to a computer. In a basic operation, the main unit of a computer controls a disk drive by using a set of commands defined by the interface. In general, a command specifies an LBA indicating a head sector of sectors to be accessed and the number of cited sectors. Receiving such a command, the HDD makes an access to the specified head sector and, then, makes an access to each of the subsequent sectors while creating a pre-fetch sequence by predicting which sectors are to be accessed. In the creation of a pre-fetch sequence, it is assumed that a data series is stored in sectors having continuous addresses. Usually, sectors having continuous addresses exist at locations to be accessed by magnetic heads having continuous head numbers or exist on a track having a track number. If data of a large amount has been stored in recording media, a pre-fetch operation is an effective operation to read out the data from the recording media. However, the recording area gets fragmented more and more so that a large data file must be stored in a plurality of small areas physically separated from each other in a state wherein the data is dispersed in the areas. In such a case, carrying out a pre-fetch operation will read but inadvertently data other than desired one. That is to say, a pre-fetch operation will not work effectively. Such a phenomenon can occur due to the fact that the HDD does not grasp the structure of a file being dealt with by the host such as a computer main unit making a request for an operation to read out data from the recording medium. In addition, a target sector of a new access request made by the host may be off from a predicted sequence of sectors. In this case, the disk drive must carry out a seek operation to find a track including the target sector containing the data specified in the request. As the tracking operation, that is, the seek operation to find the track including the target sector, is completed, the head enters a state of waiting for the sector to become accessible. In this way, it takes time to complete the tracking operation and to wait for the sector to become accessible. It is possible to keep as much data as allowed by the storage capacity of a data buffer. If the event in which the target sector of a new access is off from a predicted sequence of sectors happens consecutively or sporadically, pieces of data that have already been stored in the data buffer but are not to be used must be discarded sequentially starting with the one stored in the buffer least recently. In addition, a seek operation cannot be activated while a pre-fetching operation is being carried out. As is obvious from the above descriptions, a seek time, a rotation wait time and a seek-operation delay time caused by a wasteful pre-fetch operation can each be a time loss whereas data read out from the disk in a wasteful pre-fetch operation can be a data loss. In an ordinary disk drive, the rotating speed of the disk is raised in order to shorten the seek and rotation-wait times. This is because it is difficult to make an improvement by adopting a new access method due to the fact that there is no rule in the amount and structure of data handled by the host such as a computer. In addition, most of the conventional external storage systems such as an HDD correct errors for each sector unit normally consisting of 512 bytes. Thus, a random error occurring in each sector can be corrected. However, it is not possible to correct an error beyond a correctable domain or burst errors. In order to solve this problem, a retry operation is carried out in an attempt to confine the number of read errors within a predetermined limit. However, a retry operation is carried out to again read out data from a recording medium after a required state of waiting for a disk rotation. Thus, the operation to again read out data from a recording medium further increases the delay time. For example, a system handling AV contents may be put in a situation wherein a high transfer speed is requested for carrying out an HD (high definition) reproduction process or a special reproduction process. In such a case, there may be no time margin for carrying out a retry operation even if an irrecoverable read error is detected in a sector. At such a time, with the contemporary technology, the reproduction process is continued with the error remaining uncorrected as it is. As a result, the quality of the reproduced data deteriorates. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a diagram showing a model of the entire configuration of an HDD 10 implemented by an embodiment of the present invention; FIG. 2 is a diagram showing a typical Zone Bit Recording method; FIG. 3 is a diagram showing typical communications, which take place when the HDD 10 implemented by the embodiment writes data onto a disk in accordance with a command received from a host 50 connected to the HDD 10 by an interface 17 ; FIG. 4 is a diagram showing typical communications, which take place when the HDD 10 implemented by the embodiment reads out data from the disk in accordance with a command received from the host 50 connected to the HDD 10 by the interface 17 ; FIG. 5 is a diagram showing the internal configuration of a disk controller 13 in detail; FIG. 6 is a diagram showing a typical configuration of an ECC block provided by the embodiment; FIG. 7 is a diagram showing another typical configuration of the ECC block provided by the embodiment; FIG. 8 is a diagram showing a model of a typical disk format structure of a magnetic disk 21 using the ECC blocks shown in FIGS. 6 and 7 ; FIG. 9 is a diagram showing a model of a typical format of each sector existing on a track of the magnetic disk 21 in the HDD 10 implemented by the embodiment; FIG. 10 is a diagram showing a model of another typical sector format; FIG. 11 is a diagram showing a typical application of interleaves to the configuration of the ECC block provided by the embodiment; FIG. 12 is another diagram showing the typical application of interleaves to the configuration of the ECC block provided by the embodiment; FIG. 13 is a diagram showing a model of a disk format for an ECC block changed from zone to zone; FIG. 14 is a diagram showing another embodiment for an ECC block configuration changed from zone to zone; FIG. 15 shows a flowchart representing processing operations carried out in the disk controller 13 in a process to write data onto the disk; and FIG. 16 shows a flowchart representing processing operations carried out in the disk controller 13 in a process to read out data from the disk. detailed-description description="Detailed Description" end="lead"? |
Method and equipment for making polychlorobiphenyl nontoxic |
An equipment for making PCB nontoxic comprises: a first burn furnace 10 for burning an oil containing the PCB with auxiliary fuel: a second oxidation reaction unit 12, connecting to the first burn furnace 10 under sealing, comprising a supply source of a solution of metallic phthalocyanine derivatives and a supply source of the solution of the oxygen supply compound. |
1. A method for making polychlorobiphenyl nontoxic comprising steps of: a first oxidation step for oxidizing the polychlorobiphenyl by burn: a second oxidation step for oxidizing exhaust gas produced from the first oxidation step, which may contain dioxin, by contact with metallic phthalocyanine or derivatives thereof, and an oxygen supply compound. 2. The method for making polychlorobiphenyl nontoxic according to claim 1, wherein said first oxidation step makes the polychlorobiphenyl burn with an auxiliary fuel under supplying water. 3. The method for making polychlorobiphenyl nontoxic according to claim 1, wherein said second oxidation step makes the exhaust gas come in contact simultaneously with a solution of the metallic phthalocyanine or the derivatives thereof and a solution of the oxygen supply compound. 4. The method for making polychlorobiphenyl nontoxic according to claim 1, wherein said second oxidation step makes the exhaust gas come in contact with the solution of the metallic phthalocyanine or the derivatives thereof and then in contact with the solution of the oxygen supply compound. 5. The method for making polychlorobiphenyl nontoxic according to claim 1, wherein said oxygen supply compound is selected from the groups consisting of a hydrogen peroxide solution, an organic peroxide compound, a peroxosulfuric acid compound, a peroxotitanic acid and a peroxoboric acid. 6. The method for making polychlorobiphenyl nontoxic according to claim 1, wherein said metallic phthalocyanine derivative is represented by the following chemical formula (5), and at least two of X in the chemical formula (5) are a carboxyl group or a sulfonic acid group. 7. The method for making polychlorobiphenyl nontoxic according to claim 1, wherein said solution of the oxygen supply compound is a hydrogen peroxide aqueous solution. 8. An equipment for making polychlorobiphenyl nontoxic comprising: a first burn furnace for burning an oil containing the polychlorobiphenyl with the auxiliary fuel: a second oxidation reaction unit, connecting to the first burn furnace under sealing, comprising a supply source of the solution of the metallic phthalocyanine derivatives and a supply source of the solution of the oxygen supply compound. 9. The equipment for making polychlorobiphenyl nontoxic, wherein said second oxidation reaction unit further connecting to a neutralization reaction unit opening to outside. |
<SOH> BACKGROUND ART <EOH>PCB is excellent in insulation and fire-resistant so that is used mainly as an insulating oil and a heating medium, for widespread purposes. However, since PCB is very stable chemically, it remains for a long period of time after being discharged into environment, and causes a human a bad influence. Therefore, both of production of PCB and use thereof are forbidden, and one produced in the past is kept under sealing. PCB and secondary products using it are kept so much in a depository. If PCB is kept in a long period of time, the PCB has risk of flowing out by obsolescence of the depository. So a processing for making PCB nontoxic is desired strongly. Since it is hard to decompose, the processing for making PCB nontoxic is very difficult. But various processing methods are examined. For instance, a decomposing method of PCB by microbes is mentioned in Japanese Patent Provisional Publication No. 4-370097, and a chemical decomposing method of PCB is mentioned in Japanese Patent Provisional Publication No. 8-141107. Moreover, there is also a decomposing method of PCB by burning at high temperature. However, these former decomposing methods of PCB have certain technical or economical problems. For instance, it is unsuitable for a mass processing since a processing speed is slow, or toxic substance is included in exhaust gas after the processing, or equipment thereof is very expensive. Especially, since PCB comprises chlorine in molecular structure, dioxin is produced in decomposition reaction of PCB secondarily. It is well known that dioxin has toxicity, carcinogenicity and residual property. Therefore, it is considered that the processing which dioxin is contained in exhaust gas has a fatal defect. On the other hand, an effective method for decomposing and removing dioxin is mentioned in Japanese Patent Provisional Publication No. 2002-35772 which was applied by applicants of this patent. In the present invention, PCB is decomposed to completely nontoxic substance using the technique mentioned in Japanese Patent Provisional Publication No. 2002-35772. It is an object of the present invention to provide a processing method and equipment for PCB, which uses the simple equipment and is suitable for a quick mass processing at a low cost, and which exhaust gas emitted into atmosphere and residue dumped into natural environment are safe. |
Breath-enhanced ultrasonic nebulizer and dedicated unit dose ampoule |
A medicament delivery system comprises a nebulizer device, an open-faced mist chamber-defining element having a tubular input/output port, a tubular inhalation port connecting to the output port of the mist chamber-defining element, and a sealed unit dose ampoule adapted to fit within the mist chamber-defining element. The nebulizer device includes an ultrasonic transducer responsive to applied electrical energy to generate ultrasonic energy, an ultrasonic transmission horn between an input energy surface at an input end and an energy delivery surface at an output end. The sealed unit dose ampoule can be placed directly into the nebulizer device and acts as both the dose cup and baffle, so that the chance of spillage of drug and the number of components to be cleaned are minimized. The unit dose ampoule has a conical base to allow ultrasonic energy conducted from the ultrasonic system to be concentrated at the base of the ampoule. The inhalation port includes an inhalation valve and an exhalation valve. |
1. A medicament delivery system comprising: A. a nebulizer including a housing extending along a housing axis from a base end to an energy delivery end, said housing including therein: i. an ultrasonic transducer responsive to applied electrical energy to generate ultrasonic energy at an output surface thereof; ii. an ultrasonic transmission horn extending along said housing axis between an input energy surface at an input end and an energy delivery surface at an output end, said input energy surface being acoustically coupled to said output surface of said transducer, said horn being adapted to transmit ultrasonic energy applied at said. input energy surface along said housing axis to said energy delivery surface, B. an open-faced mist chamber-defining element extending along a chamber axis from an open-faced coupling end and said mist chamber-defining element including a tubular input/output port extending therefrom along a port axis, said port axis being angularly offset from said chamber axis, C. coupling means for selectively coupling said open-faced coupling end of said mist chamber-defining element to said energy delivery end of said housing whereby said interior volume of said mist chamber-defining element is opposite said energy delivery surface of said horn and said chamber axis is substantially parallel to said housing axis, D. a tubular inhalation port extending between a user end and a device end, E. a bidirectioinal valve assembly having a first port coupled to said device end of said inhalation port, a second port coupled to said port of said mist chamber-defining element and a third port coupled to points exterior to said bidirectioinal valve assembly, wherein said valve assembly defines a unidirectional airflow path only from said interior volume of said mist chamber-defining element to said user end of said inhalation port when the pneumatic pressure in said inhalation port is lower than the pneumatic pressure in said interior volume of said mist chamber-defining element, and wherein said valve assembly defines a unidirectional airflow path only from said user end of said inhalation port to said exterior points, when the pneumatic pressure in said inhalation port is greater than the pneumatic pressure in said interior volume of said mist chamber-defining element. 2. A medicament delivery system according to claim 1, further comprising: a cup-shaped medicament ampoule having an open-faced interior region defined by a base member extending from an open top ring at a top end along an ampoule axis to a closed end opposite said top end, wherein said closed end has an outer surface complimentary to said energy delivery surface of said ultrasonic transmission horn, and wherein said ampoule is adapted to fit within said mist chamber-defining element with said outer surface of said closed end of said ampoule fitting in intimate contact with said energy delivery surface of said ultrasonic transmission horn. 3. A medicament delivery system according to claim 2 wherein said ampoule includes a medicament disposed in said interior region of said ampoule and wherein said open top ring of said ampoule is spanned by a sheet member whereby said interior region of said ampoule is closed. 4. A medicament delivery system according to claim 3 wherein said sheet member is removable. 5. A medicament delivery system according to claim 3 wherein said sheet member is frangible. 6. A medicament delivery system according to claim 1 wherein said mist chamber-defining element is dome-shaped. 7. A medicament delivery system according to claim 1 wherein said port axis is offset from said chamber axis by an angle in the-range 35 to 55 degrees. 8. A medicament delivery system according to claim 1 wherein said port axis is offset from said chamber axis by 45 degrees. 9. A medicament delivery system according to claim 1 wherein said energy delivery surface is cone-shaped. 10. A medicament delivery system according to claim 1 wherein said bi-direction valve assembly is a discrete assembly adapted for removable coupling of said second port of said bi-direction valve assembly. 11. A medicament delivery system wherein said bi-direction valve assembly is integral with said port of said mist chamber-defining element. 12. A medicament delivery system according to claim 1 wherein said mist chamber-defining element is transparent. 13. A medicament delivery system according to claim 1 wherein said mist chamber-defining element is translucent. 14. A medicament delivery system according to claim 1 wherein said mist chamber-defining element is opaque. 15. A medicament delivery system according to claim 1, further comprising: A. an ampoule sensors including means for sensing the presence of a medicament ampoule in a predetermined position within said mist chamber-defining element and in response thereto, for generating a control signal representative thereof, B. means responsive to said control signal to allow electrical energy to be applied to said transducer, and for preventing application of electrical energy otherwise. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Nebulizers are well known for dispensing medicament to the lungs of a patient for treating asthma, for example. A typical prior art nebulizer assembly for such therapeutic purposes includes a nebulizer which contains an electrically driven ultrasonic energy source and a dose cup acoustically coupled to receive ultrasonic energy from the source. A domed element is removably disposed over the dose cup, establishing a substantially closed mist chamber-defining element therein. An inhalation port extends from the domed element, permitting a user to inhale the contents of the mist chamber-defining element. The conventional practice of nebulizing an aqueous solution in ultrasonic (or jet) nebulizers, involves a first step of removing the domed element (permitting user access to the dose cup), followed by breaking an ampoule or vial containing the medicament, and introducing the contents into a dose cup or chamber. The domed element is then replaced, and the ultrasonic energy source is activated, whereby the ultrasonic energy is transmitted to the dose cup, where it nebulizes the medicament. A user may then inhale via the inhalation port, as desired. The method of introducing the medicament to the dose cup involves prolonged handling of the medicament by the patient and therefore may lead to hygiene issues and volume loss due to spillage or incomplete emptying of the ampoule. A further issue is the number of components which require cleaning following nebulization—dose cup, domed element, inhalation ports of the inhalation port, for example. It is an object of this invention to provide an improved nebulizer apparatus and method which minimizes spillage of drug and the number of components to be cleaned. Another object is to provide an improved nebulizer. Most conventional nebulizers allow free flow of air through a dose chamber during nebulization, which results in the exhalation of the patient forcing nebulized mist back into the dose chamber and device during exhalation. As a consequence, a large proportion of the dose condenses on the inside of the device and is therefore not delivered to the lung. It is another object of this invention to provide more efficient air control during inhalation and particularly exhalation, to significantly improve nebulizer performance. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a medicament delivery system. The medicament delivery system comprises a nebulizer, an open-faced mist chamber-defining element, coupling means for selectively coupling the coupling end of the mist chamber-defining element to the energy delivery end of the housing, a tubular inhalation port extending between a user end and a device end, and a bidirectioinal valve assembly. In a preferred form of the invention, the nebulizer includes a housing extending along a housing axis from a base end to an energy delivery end. The housing includes an ultrasonic transducer responsive to applied electrical energy to generate ultrasonic energy at an output surface, and an ultrasonic transmission horn extending along the housing axis between an input energy surface and an output end. The input energy surface is acoustically coupled to the output surface of the transducer. The horn is adapted to transmit ultrasonic energy applied at the input energy surface along the housing axis to the energy delivery surface. The open-faced mist chamber-defining element extends along a chamber axis from an open-faced coupling end. The mist chamber-defining element includes a tubular input/output port extending along a port axis, with the port axis being angularly offset from the chamber axis. The chamber-defining element is selectively couplable to the energy delivery end of the housing so that the interior volume of the mist chamber is opposite the energy delivery surface of the horn and the chamber axis is substantially parallel to the housing axis. Preferably, the chamber-defining element is dome-shaped, so that when its open face is coupled to the housing, it defines the substantially closed mist chamber. The bidirectioinal valve assembly has a first port coupled to the device end of the inhalation port, a second port coupled to the port of the mist chamber-defining element and a third port coupled to points exterior to the bidirectioinal valve assembly. The valve assembly defines a unidirectional airflow path only from the interior volume of the mist chamber to the user end of the inhalation port when the pneumatic pressure in the inhalation port is lower than the pneumatic pressure in the interior volume of the mist chamber. The valve assembly also defines a unidirectional airflow path only from the user end of the inhalation port to the exterior points when the pneumatic pressure in the inhalation port is greater than the pneumatic pressure in the interior volume of the mist chamber. The medicament delivery system further includes a cup-shaped medicament ampoule having a removable (for example, by peeling off a foil cover) seal adapted to fit within the mist chamber-defining element. The ampoule has an open-faced interior region defined by a base member. The interior region extends from an open top ring at a top end along an ampoule axis to a closed end opposite the top end, wherein the closed end has an outer surface complimentary to the energy delivery surface of the ultrasonic transmission horn. The ampoule is adapted to fit within the mist chamber-defining element with the outer surface of the closed end of the ampoule fitting in intimate contact with the energy delivery surface of the ultrasonic transmission horn. The ampoule further includes a medicament disposed in the interior region of the ampoule and wherein the open top ring of the ampoule is spanned by a sheet member whereby the interior region of the ampoule is closed. The sealed unit dose ampoule (filled with the relevant medicament) is positionable into the device (with its seal intact), and when the seal is removed, the ampoule acts as both a dose cup negating the need for a separate baffle. With that configuration, drug handling is limited, the likelihood of spillage of the medicament is reduced, and consequently a consistent dose can be delivered. In a preferred form, the ampoule is disposable, minimizing the number of components to be cleaned. The ampoule of the present invention is preferably essentially a small, thin walled cup. In one preferred embodiment, the unit dose ampoule includes an upper screw thread portion, a location ring and a conical base. The upper screw thread portion is adapted to be screw connected with the open-faced end of the mist chamber-defining element. The location ring allows the ampoule to be positioned within the nebulizer device. The base is preferably conical shaped to allow the ultrasonic energy conducted from the ultrasonic system to be concentrated at the base of the ampoule. This design also enables fluid returning of activated medicament from the sides of the ampoule to the point at which all the ultrasonic energy is concentrated. The ampoule has a predetermined volume designed to contain a required dose of medicament. The inhalation port includes an inhalation valve, a main chamber and an exhalation valve. During inhalation by a user, the inhalation valve opens to allow passage of aerosol mist into the main chamber of the inhalation port and subsequently into the patient. At the same time the exhalation valve remains closed. During exhalation, the exhalation valve becomes operational to allow the breath to pass out of the inhalation port without entering the mist chamber, at the same time the inhalation valve remains closed to prevent breathing back into the dose unit. The present invention is applicable for both solutions and suspensions. Drug applications may include all nebulized formulations, particularly in the following therapeutic areas—Asthma, COPD, Cystic Fibrosis, infections of any type responsive to antibiotic treatment, and pain treatment of any type. |
Use of milk serum apoproteins in the prophylaxis or treatment of microbial or viral infection |
The present invention relates to use of a milk apoprotein or a mixture thereof to prevent or treat microbial or viral infection of the human or animal body. It is believed that this is achieved by inhibiting adhesion of potential pathogens. More preferably, at least one milk apoprotein or a mixture thereof is administered, simultaneously or sequentially, with either or both of at least one free fatty acid or a mixture thereof or a monoglyceride thereof; and/or at least one organic acid or a salt or ester thereof or a mixture thereof. The active agent(s) may be delivered by means of a pharmaceutically acceptable delivery system which includes parenteral solutions, ointments, eye drops, nasal sprays, intravaginal devices, surgical dressings, medical foods or drinks, oral healthcare formulations and medicaments for mucosal applications. |
1-32. (cancelled) 33. A pharmaceutically acceptable delivery system comprising at least one milk apoprotein, or a mixture thereof, in a pharmaceutically acceptable carrier. 34. A delivery system according to claim 33, in which the, or each, milk apoprotein is a milk apolipoprotein. 35. A delivery system according to claim 34, in which the, or each, milk apolipoprotein is derived from a milk lipoprotein selected from beta-lactoglobulin, fat globule membrane and alpha-lactalbumin or a mixture thereof. 36. A delivery system according to claim 33, in which the milk apoprotein or the mixture thereof is prepared by hydrolysing milk serum or milk whey with an enzyme(s); denaturing the enzyme(s); and separating the apoprotein(s)-rich fraction. 37. A delivery system according to claim 36, in which the enzyme is a lipase. 38. A delivery system according to claim 33, in which the milk apoprotein or the mixture thereof is prepared by hydrolysing milk serum or milk whey with an enzyme(s). 39. A delivery system according to claim 38, in which the enzyme is a lipase. 40. A delivery system according to claim 33, in which the milk is cow or goat milk. 41. A delivery system according to claim 33, further comprising at least one free fatty acid or a mixture thereof; or a monoglyceride thereof, or a mixture thereof. 42. A delivery system according to claim 41, in which the, or each, fatty acid is saturated or unsaturated and has a hydrocarbon chain with an even number of carbon atoms of from C4-C24, or a mixture thereof. 43. A delivery system according to claim 42, in which the, or each, unsaturated fatty acid has a hydrocarbon chain with C14-C24. 44. A delivery system according to claim 41, in which the fatty acid is selected from palmitoleic, oleic, linoleic, alpha and gamma linolenic, arachidonic, eicosapentanoic and tetracosenoic acids and their monoglycerides, or a mixture thereof. 45. A delivery system according to claim 41, in which the, or each, saturated fatty acid has a hydrocarbon chain with C4-C18. 46. A delivery system according to claim 41, in which the fatty acid is selected from butyric, isobutyric, succinic, caproic, adipic, caprylic, capric, lauric, myristic, palmitic and stearic acids and their monoglycerides, or a mixture thereof. 47. A delivery system according to claim 33, further incorporating at least one organic acid or a salt or ester thereof, or a mixture thereof. 48. A delivery system according to claim 47, in which the organic acid is selected from glycolic, oxalic, lactic, glyceric, tartronic, malic, maleic, fumaric, tartaric, malonic, glutaric, propenoic, cis or trans butenoic and citric acids or their salts or esters, or a mixture thereof. 49. A delivery system according to claim 33, further incorporating an anti-oxidant. 50. A delivery system according to claim 49, in which the anti-oxidant is alpha-tocopherol. 51. A delivery system according to claim 33, in the form of a solution for parenteral infusion for systemic treatment or prevention of infection. 52. A delivery system according to claim 33, in the form of an ointment for topical application in the prevention or treatment of skin infection. 53. A delivery system according to claim 33, in the form of an intravaginal cream or gel or a pessary for preventing or treating recurring Candida albicans infection. 54. A delivery system according to claim 33, in the form of a surgical dressing for use in the prevention or treatment of infection. 55. A delivery system according to claim 33, in the form of a medicament for mucosal application to the eye, nose, mouth, intestine or genitalia. 56. A delivery system according to claim 55, in the form of an eye drop for the prevention or treatment of infections of the eye. 57. A delivery system according to claim 55, in the form of a nasal spray for inhibiting transfer of antibiotic resistant organisms from a carrier. 58. A delivery system according to claim 33, in the form of a food or drink for use as a prophylactic agent against intestinal infection. 59. A delivery system according to claim 55, in the form of an oral healthcare formulation selected from a toothpaste, chewing gum, mouthwash or other dentifrice to improve dental hygiene or as a prophylactic agent against oral disease. 60. A delivery system according to claim 38, in which the hydrolysed milk serum or milk whey is present in a concentration range of 0.5 to 25 mg/ml. 61. A delivery system according to claim 33, in which the milk apoprotein, or the mixture thereof, is present in a concentration range of 0.5-10 mg/ml. 62. A delivery system according to claim 61, in which the milk apoprotein, or the mixture thereof, is present in a concentration range of 3-7 mg/ml. 63. A delivery system according to claim 41, in which the free fatty acid, or the monoglyceride thereof; or the mixture thereof, is present in a concentration range of 0.5-5 mg/ml. 64. A delivery system according to claim 47, in which the organic acid or the salt or ester thereof, or the mixture thereof, is present in a concentration range of 0.5-5 mg/ml. 65. A delivery system according to claim 41, in which the milk apoprotein or the mixture thereof; and the free fatty acid or the monoglyceride thereof, or the mixture thereof are administered either simultaneously or sequentially, within 6 hours in either order. 66. A delivery system according to claim 47, in which the milk apoprotein or the mixture thereof; and the organic acid or the salt or ester thereof or the mixture thereof, are administered either simultaneously or sequentially within 6 hours in either order. 67. A delivery system according to claims 41, further incorporating at least one organic acid or a salt or ester thereof, or a mixture thereof; and in which the milk apoprotein or the mixture thereof; the free fatty acid or the monoglyceride or the mixture thereof; and the organic acid or the salt or ester thereof or the mixture thereof, are administered either simultaneously or sequentially within 6 hours of each other, in any order. 68. A delivery system according to claim 33, for cosmetic skincare. 69. A product comprising: (a) at least one milk apoprotein, or a mixture thereof, and (b) at least one free fatty acid or a mixture thereof, or a monoglyceride, or a mixture thereof. 70. A product according to claim 69, in which the, or each, milk apoprotein is a milk apoprotein selected from the group consisting of beta-lactoglobulin, fat globule membrane and alpha-lactalbumin or a mixture thereof. 71. A product according to claim 69, in which the, or each, fatty acid is selected from the group consisting of palmitoleic, oleic, linoleic, alpha and gamma linolenic, arachidonic, eicosapentanoic, tetracosenoic, butyric, isobutyric, succinic, caproic, adipic, caprylic, capric, lauric, myristic, plamitic and stearic acids and their monoglycerides, or a mixture thereof. 72. A method for inhibiting adhesion of potential pathogens in or on a surface of a human or animal body, said method comprising administering to said human or animal an effective amount of a milk apoprotein or a mixture thereof. 73. A method according to claim 72, in which the, or each, milk apoprotein is a milk apolipoprotein selected from the group consisting of beta-lactoglobulin, fat globule membrane and alpha-lactalbumin or a mixture thereof. 74. A method according to claim 72 further comprising administering at least one free fatty acid or a mixture thereof; or a monoglyceride thereof, or a mixture thereof. 75. A method according to claim 74, in which the, or each, fatty acid is selected from the group consisting of palmitoleic, oleic, linoleic, alpha and gamma linoleic, arachidonic, eicosapentanoic, tetracosenoic, butyric, isobutyric, succinic, caproic, adipic, caprylic, capric, lauric, myristic, palmitic and stearic acids and their monoglycerides, or a mixture thereof. |
<SOH> BACKGROUND ART <EOH>Milk is a whitish liquid that is produced from the mammary glands of mature female mammals after they have given birth. Mammals are warm-blooded vertebrates of the Class Mammalia, including humans, the mammals, for the purposes of the present invention, being more preferably hoofed, even-toed mammals of the Suborder Ruminantia, such as cattle, sheep, goats, deer and giraffes. Milk from cattle and goats are the preferred sources of milk apoproteins of the present invention, merely because milk from these sources is readily available on a commercial scale. Milk serum is a term commonly used in the dairy industry to describe the clear liquid matrix within which casein micelles and butterfat globules are suspended. Milk serum from ruminants contains the milk sugar lactose; a variety of proteins including milk antibodies, lactoferrin and enzymes; and a variety of lipoproteins including beta-lactoglobulin. Milk serum is a preferred source of milk apoproteins. Cow's milk is processed in the dairy industry to obtain either butter or cheese. Mechanical agitation is used to break the milk-fat globules to obtain butter, and casein is precipitated to obtain curd from which cheese is manufactured. The liquid residue remaining after these processes is commonly referred to as milk whey. Milk whey is essentially the milk serum, with an increased lipoprotein content arising mainly from the fat globule membrane. Milk whey is a preferred source of milk apoproteins. The term “milk serum apoprotein” as used herein is intended to embrace milk apoproteins derived from milk serum or milk whey. There are a variety of different lipoproteins and glycoproteins in milk serum, all of which are characterised by a protein back-bone, to which lipids and/or carbohydrates are conjugated. Enzymatic hydrolysis may be used to remove the lipids and/or carbohydrates from this protein back-bone, to prepare the corresponding apoprotein. Although milk serum apoproteins have been isolated, there are no known medical uses for such milk serum apoproteins. Lipids, or fats, include triesters of fatty acids, which may be the same or different, and glycerol, also described as tri-acylglycerols or triglycerides. Further hydrolysis may be used to break these ester bonds, thus liberating free fatty acid(s) from the tri-acylglycerols. The use of calf pregastric lipase to liberate free fatty acids from milk lipids is reported by Cynthia Q Sun et al (Chemico-Biological Interactions 140 (2002), pp185-198). This author reports the growth inhibitory properties of various free fatty acids against Enterococci , which are gram-positive, and coliform bacteria, which are gram-negative but is silent on the role of milk serum apoproteins. Free fatty acids are known to exhibit potent antimicrobial and antiviral activity. In particular, linoleic, linolenic, caprylic and caproic acids were reported by Schuster et al (Pharmacology and Therapeutics in Dentistry 5: pp25-33; 1980) to inhibit the dental caries organism, Streptococcus mutans , and to effect a general reduction in dental plaque. According to the author, bacteria classified as grain negative are most sensitive while gram positives are least affected. Additionally, Halldor Thormar et al (Antimicrobial Agents and Chemotherapy; January 1987, pp 27-31) review the antiviral properties of free fatty acids and their monoesters, demonstrating the efficacy of polyunsaturated long-chain fatty acids and medium-chain saturated fatty acids (and their monoglyceride esters) against enveloped viruses and their relative inactivity against nonenveloped viruses, the viricidal effect being possibly by destabilising the viral envelope itself. More recently, the bactericidal activity of free fatty acids was reviewed by R. Corinne Sprong et al (Antimicrobial Agents and Chemotherapy, April 2001, pp 1298-1301)—C10:0 and C12:0 fatty acids were found to be powerful bactericidal agents. The fungicidal properties of C10:0 and C12:0 free fatty acids and their monoglycerides was described by Gudmundur Bergsson et al (Antimicrobial Agents and Chemotherapy, November 2001, pp 3209-3212). Many potentially pathogenic bacteria are common commensals of the skin, hair and mucus membranes—they colonise these areas by adhering to the surface epithelial cell layer but are normally kept in check by the host's secretory immune system in mucus and sweat. Disease caused by these endogenous species usually arises as a result of some debilitation in the host's secretory immune capability, which allows these endogenous pathogens to proliferate. Adhesion of pathogenic bacteria to host tissue is generally accepted as being the first stage in pathogenesis, so that the ability to block adhesion should be useful in preventing infection. The mechanism of such adhesion is varied and many organisms employ a multiplicity of both specific and non-specific factors. For example, Staphylococci secrete an extracellular teichoic acid, which binds specifically to fibronectin; Candida species employ a glycocalyx of mannoprotein; and Streptococci make use of water insoluble glucans to colonise the teeth. Because of the variety of these factors, it has long been considered impossible to devise a single inhibitor, which would be effective against the wide range of potentially pathogenic species. The use of antibodies derived by vaccination of some donor animal has been attempted in many situations but, because of the built-in specificity, the therapeutic use of these antibodies is confined to use against the species to which they have been generated. In all of the above published data, the use of free fatty acids to inhibit growth of a wide range of bacteria, fungi and viruses is disclosed but there are no known published data disclosing or suggesting their efficacy when administered with one or more milk apoproteins in the inhibition of adhesion and/or growth of potential pathogens in human and animal healthcare. The common practice in medical and veterinary care of infection is the application of an antibiotic substance designed to inhibit the infectious agent, which may be fungal, bacterial (both embraced by the term “microbial”) or viral. In long-term use, many antibiotic substances have lost their potency due to the evolution of resistance by the infectious agent. The problem of antibiotic resistance is most acute in post-operative situations where the infectious agent is a common inhabitant of the skin and respiratory tract and, as such, it may have been exposed to frequent and varied antibiotics over time, allowing it to evolve resistance to these substances. Large numbers of these normally innocuous agents may be disseminated during surgical or nursing procedures and may give rise to infections when the immune tolerance of the patient has been weakened by disease or extended medical intervention; such infections are frequently described as nosocomial infections. One such nosocomial infection is commonly referred to as MRSA (methicillin resistant Staphylococcus aureus ). Staphylococcus aureus is a common inhabitant of the respiratory tract of many individuals, where it is carried asymptomatically without normally causing infection. Because of its ubiquitous nature, it is thought to have been exposed to many of the commonly used antibiotic substances, and strains now exist which are resistant to all commonly used antibiotics including methicillin. Vancomycin is ‘the drug of last resort’ in MRSA, but strains have recently emerged that are resistant to vancomycin. In addition, vancomycin resistant Enterococcus faecalis (VREF) is a common inhabitant of the gut and may be disseminated from there during surgical procedures, giving rise to other nosocomial infection. Horizontal gene transfer is a biological term used to describe the potential transfer of genetic resistance from one species to another. The transfer of antibiotic resistance from species such as VREF to pathogenic species such as Clostridium difficile (Pseudomembranous colitis) is a potentially disastrous event and one which gives cause for great concern among the medical profession. There is therefore a great need for new antimicrobial substances, which may be used to treat such antibiotic resistant infections and others that are refractive to conventional treatments, and for new antiviral substances to treat viral infections for which there are currently few effective therapeutic remedies. It is an object of the present invention to retard, preferably block, adhesion of pathogenic organisms and, thus, prevent or treat microbial or viral infection of the human or animal body. It is a further object of the present invention to combine the retarding or blocking of adhesion with an inhibition of growth, thereby achieving an even greater utility. It is a still further object of the present invention to achieve these utilities by the use of a benign material such as, but not limited to, milk serum since this facilitates much more frequent use than is considered prudent with many aggressive chemically based medicines. |
Use of microbiology non-viral substances for treating acne |
This is to describe the use of at least one molecular-biologically prepared non-viral active agent (antisense oligonucleotides, ribozymes, stabilized ribozymes, aptamers, mirror aptamers, chimeric RNA/DNA oligonucleotides, naked plasmid-DNA or liposomally encapsulated DNA), especially an antisense oligonucleotide having specificity for a nucleic acid target sequence of the genes, which codes for steroid hormone receptors and/or steroid hormone metabolizing enzymes, especially for the androgen receptor and/or the 5α-reductase, for the treatment of acne and acneiform dermatoses including rosacea. For this purpose, preferably specific antisense oligonucleotides and degenerated sequences thereof are selected and preferably introduced by a liposome-mediated transfection into the target cells, especially human sebocytes and/or keratinocytes. In these target cells, a specific inhibition of the androgen-induced, especially of the testosterone-induced stimulation of the sebocyte and/or keratinocyte proliferation by the described antisense oligonucleotides has been determined and evaluated. The effects according to the invention have been detected by way of example with the aid of the sebocyte cell line SZ95 and primary keratinocytes of the skin. |
1. Use of at least one molecular-biologically prepared non-viral active agent selected from antisense oligonucleotides, stabilized ribozymes, aptamers, mirror aptamers, chimeric RNA/DNA oligonucleotides, naked plasmid-DNA or liposomally encapsulated DNA, for the treatment of acne and acneiform dermatoses including rosacea. 2. Use according to claim 1, characterized in that an antisense oligonucleotide having specificity for a nucleic acid target sequence of a gene which codes for steroid hormone receptors or steroid hormone metabolizing enzymes is used. 3. Use according to claim 2, characterized in that the antisense oligonucleotide codes for the androgen receptor and/or the 5α-reductase. 4. Use according to claim 1, characterized in that at least one antisense oligonucleotide is selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2 and degenerated sequences thereof. 5. Use according to claim 1, characterized in that the at least one antisense oligonucleotide is complementary to a ribonucleic acid sequence derived from a gene sequence coding for the androgen receptor and/or the5α-reductase. 6. Use according to claim 5, characterized in that the antisense oligonucleotide is complementary to a single-strand RNA or single-strand DNA or a DNA inside a duplex strand. 7. Use according to any one of claims 1 to 6, characterized in that the antisense oligonucleotide is chemically modified. 8. Use according to claim 1, characterized in that the nucleic acid target sequence is provided in epithelial cells, especially in human epithelial cells. 9. Use according to claim 1, characterized in that the nucleic acid target sequence is provided in cells of the human skin. 10. Use according to claim 8 or 9, characterized in that the nucleic acid target sequence is provided in human sebocytes and/or keratinocytes. 11. Use according to claim 10, characterized in that the target cells are human sebocytes and/or keratinocytes. 12. Use according to any one of the preceding claims, characterized in that the at least one antisense oligonucleotide is introduced into the target cells by liposome-medicated transfection. 13. Use according to any one of the preceding claims, wherein the antisense oligonucleotide is combined with at least one further conventional anti-acne active agent. 14. Use according to any one of the preceding claims, wherein an oral and/or topical application is effected. 15. Use according to any one of claims 11 and 12 for the preparation of a pharmaceutical composition having at least one of the features listed in claims 1 to 10 together with a pharmaceutically acceptable carrier and further adjuvants where appropriate. 16. Use according to any one of the preceding claims for the examination, treatment and/or therapy of acne and acneiform dermatoses including rosacea. 17. Use according to claim 15 for the preparation of products for the examination, treatment and/or therapy of acne and acneiform dermatoses including rosacea. 18. Use of the products obtained according to claim 17 for modifying other cells or for modifying organisms. |
New drug |
CD44, the receptor for hyaluronic acid, has complex functions in cellular physiology, cell migration and tumour metastasis. The inventors have previously found that human CD44 receptor overexpression in mouse fibrosarcoma cells inhibits subcutaneous tumour growth in mice [Kogerman et al., Oncogene 1997; 15:1407-16; Kogerman et al., Clin Exp Metastasis 1998; 16:83-93]. Here it is demonstrated that a tumour growth inhibitory effect of CD44 is caused by block of angiogenesis. Furthermore, the inventors have found that soluble recombinant CD44 hyaluronic acid binding domain (CD44HABD) inhibits angiogenesis in vivo in cLick and mouse and thereby inhibits human tumour growth of various origins. The anti-angiogenic effect of CD44-HABD is independent of hyaluronic acid (HA) binding, since non-HA-binding mutants of CD44HABD still maintain anti-angiogenic properties. The invention discloses soluble CD44 recombinant proteins as a novel class of angiogenesis inhibitors based on targeting of vascular cell surface receptor. A method of block of angiogenesis and treatment of human tumours using recombinant CD44 proteins as well as their analogues is disclosed. As a further embodiment of the invention, methods for screening for new drug targets using CD44 recombinant proteins and their analogues is presented. |
1. A method for the manufacturing of a medicament for treating states related to the inhibition of angiogenesis and/or endothelial cell proliferation comprising using a molecule comprising a non-HA-binding variant of the CD44-hyaluronic acid binding domain (CD44-HABD), as or non-HA-binding analogues, recombinant and mutated variants or fragments thereof. 2. The method according to claim 1, whereby the CD44-HABD comprises at least one mutation, thereby rendering it non-HA-binding. 3. The method according to claim 2, wherein the at least one mutation is chosen from F34A, F34Y, K38R, R41A, Y42F, Y42S, R46S, E48S, K54S, Q65S, K68S, R78K, R78S, Y79F, Y79S, N100A N100R, N101S, Y105F, Y105S, S112R, Y114F, F119A and F119Y. 4. The method according to claim 1, whereby the CD44-hyaluronic acid binding domain has a homology to the sequence SEQ ID NO:2 of at least 55%. 5. The method according to claim 1, whereby the recombinant variant is a fusion protein having a CD44-HABD part and a GST-part, wherein the CD44-HABD-part is in a non-HA-binding form. 6. The method according to claim 1, whereby the molecule comprising a non-HA-binding variant of the CD44-hyaluronic acid binding domain is chosen from the group: human CD44-HABD (SEQ ID NO:2), dog CD44-HABD (SEQ ID NO:4), chick CD44-HABD (SEQ ID NO:6), human CD44-HABD-R41A (SEQ ID NO:8), human CD44-HABD-R78Y79S (SEQ ID NO:10), CD44-HABD-R41AR78SY79S (SEQ ID NO: 12), CD44-HARD (21-100) (SEQ ID NO:23) and CD44-HABD (61-100) (SEQ ID NO:26), wherein the sequences further comprise at least one modification thereby making them non-HA-binding. 7. The method according to claim 1, wherein the molecule is of human, dog, chick, primate, rat or mouse origin. 8. The method according to claim 1, whereby the state to be treated is chosen from the following group: ocular diseases causing blindness, or impaired vision, states of chronical inflammation, in psoriasis, atherosclerosis, restenosis, in cancer growth and metastasis, all forms of cancer diseases and tumors, and in hemangioma. 9. A method for targeting of endothelial cells comprising usung a molecule comprising a variant of the CD44-hyaluronic acid binding domain, or analogues, recombinant and mutated variants, or fragments thereof. 10. The method according to claim 9, whereby the molecule further comprises a moiety showing chemotherapeutical and/or gene therapeutical properties. 11. A recombinant molecule comprising a CD44-HABD-part, and a part chosen from (i) a GST-part (ii) a moiety showing chemotherapeutical properties, (iii) a moiety showing genetherapeutical properties, and (iv) a tag chosen from IgG, IgM, IgA, His, HA, FLAG, c-myc and EGFP, wherein the CD44-HARD-part is mutated by at least one mutation that makes it non-HA-binding. 12. The recombinant molecule according to claim 11, whereby the CD44-HABD-part is defined by a modified variant of any one of the amino acid sequences SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:23, or SEQ ID NO:26. 13. The recombinant molecule according to claim 11, wherein the CD44-HABD-part is encoded by a sequence having at least 55% homology. 14. The recombinant molecule according claim 11, wherein said recombinant molecule is for medical use. 15. A pharmaceutical composition comprising at least one molecule according to claim 11, in mixture or otherwise together with at least one pharmaceutically acceptable carrier or excipient. 16. A method for the treatment of a tumor or another related disease in a subject, comprising administrating a pharmaceutical dose of a molecule according to claim 11. 17. A method for screening for a binding partner for a molecule according to claim 11, comprising the steps of: a) providing the molecule comprising the CD44-hyaluronic acid binding domain; b) contacting a potential binding partner to said molecule; and c) determining the effect of said molecule on said potential binding partner. 18. The method according to claim 17, whereby the potential binding partner is chosen from the group comprising, glycoproteins, proteoglycans, heparan sulphates, lipids, glycans, glycosides and saccharides. 19. The method according to claim 17, whereby the potential binding partner is a receptor molecule, a part of a receptor molecule, a molecule binding to a cell surface receptor molecule or a molecule located at the cell surface without being a receptor molecule. 20. A binding partner for a molecule found by the method according to claim 17. 21. A kit comprising, in separate vials, the molecule according to claim 11, and the potential a binding partner of claim 20. 22. The method according to claim 3, wherein the at least one mutation is selected from the group consisting of R41A, R78S and Y79S. 23. The method according to claim 4, whereby the CD44-hyaluronic acid binding domain has a homology to the sequence SEQ ID NO:2 of at least 65%. 24. The method according to claim 4, whereby the CD44-hyaluronic acid binding domain has a homology to the sequence SEQ ID NO:2 of at least 75%. 25. The method according to claim 8, wherein the ocular diseases causing blindness, or impaired vision is selected from the group consisting of macular degeneration, diabetic retinopathy, and states of retinal hypoxia. 26. The method according to claim 8, wherein the state of chronical inflammation is rheumatoid arthritis. 27. The method according to claim 8, wherein the forms of cancer disease and tumors comprise cancer of breast, prostate, colon, lung, skin, liver, brain, ovary, testis, skeleton, epithelium, endothelium, pancreas, kidney, muscle, adrenal gland, intestines, endocrine glands, oral cavities, head, neck or other solid tissue origin, or being any form of leukemia. 28. The method according to claim 11, wherein the at least one mutation is chosen from F34A, F34Y, K38R, R41A, Y42F, Y42S, R46S, E48S, K54S, Q65S, K68S, R78K, R78S, Y79F, Y79S, N100A, N100R, N101S, Y105F, Y105S, S 112R, Y114F, F119A, and F119Y, 29. The method according to claim 11, wherein the at least one mutation is chosen from R41A, R78S and Y79S. 30. The recombinant molecule according to claim 13, wherein the CD44-HABD-part is encoded by a sequence having at least 65% homology. 31. The recombinant molecule according to claim 13, wherein the CD44-HABD-part is encoded by a sequence having at least 75% homology. 32. The recombinant molecule according to claim 13, wherein the CD44-HABD-part is encoded by a sequence being any one of the nucleotide sequences: SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, or SEQ ID NO:11, whereby the nucleotide sequences are in a modified form. |
<SOH> TECHNICAL BACKGROUND <EOH>The formation of new blood vessels by angiogenesis is a central event in many different pathological states, including ocular diseases causing blindness, such as macular degeneration, diabetic retinopathy and states of retinal hypoxia, states of chronical inflammation, such as rheumatoid arthritis, in psoriasis, atherosclerosis, restenosis, as well as in cancer growth and metastasis. In addition, hemangioma is caused by uncontrolled proliferation of endothelial cells. Given that many of these diseases are of a chronical nature and presently lack satisfactory medicaments, makes the search for treatments and drugs against these diseases very important. To this end, an agent blocking angiogenesis has the potential to constitute a medicament for all these common angiogenesis- (and/or endothelial cell-)dependent diseases. One interesting target for drugs against diseases of this kind has been CD44 (Naot et al., Adv Cancer Res 1997;71 :241-319). CD44 is a cell surface receptor for the large glycosaminoglycan of the extracellular matrix hyaluronic acid (HA) [Aruffo et al., Cell 1990; 61:1303-13]. CD44 plays a role in various cellular and physiological functions, including adhesion to and migration on HA, HA degradation and tumour metastasis. The CD44 receptor shows a complex pattern of alternative splicing in its variable region of the extracellular domain [Screaton et al., PNAS 1992; 89: 12160-4]. CD44 is able to bind matrix metalloproteinase-9 (MMP-9) and can thereby localize MMP-9 to the cellular membrane, which may in part explain its activity in promoting tumour cell invasion and metastasis [Yu, 1999 #3]. Among patent references disclosing CD44 and its connection to diseases described above may U.S. Pat. No. 6025138, U.S. Pat. No. 5902795, U.S. Pat. No. 6150162, U.S. Pat. No. 6001356, U.S. Pat. No. 5990299 and U.S. Pat. No. 5951982 be mentioned. WO94/09811 describes the use of CD44 in treating inflammation or detecting cancer metastasis of hematopoietic origin. Use of CD44 for inhibiting solid tumor growth or angiogenesis is not disclosed. WO 99/45942 discloses the use of HA-binding proteins and peptides including CD44 to inhibit cancer and angiogenesis-dependent diseases. CD44 is mentioned as one example of a long list of HA-binding proteins. In both publications the use of C144 is limited to its ability to bind hyaluronic acid. Ahrens et al. (Oncogene 2001; 20; 3399-3408) discloses that soluble CD44 inhibits melanoma tumour growth by blocking the binding of tumour cell surface CD44 to hyaluronic acid. Thus, this work teaches a hyaluronic acid binding dependent mechanism for the CD44 effect directly on melanoma tumour cell growth. Alpaugh et al. (Exp. Cell Res. 261, 150-158 (2000)) discloses myoepithelial-specific CD44 and its antiangiogenic properties. This study deals with HA-binding properties of CD44. Bajorath (PROTEINS: Structure, Function, and Genetics 39: 103-111 (2000)) discloses CD44 and its binding to HA, cell adhesion and CD44-signalling. Moreover, CD44 mutagenesis experiments are disclosed involving among others the well-established non-HA-binding mutations R41A and R78S, and their impact on CD44-binding to HA. Thus, the prior art discloses the potential use of CD44 to specify that any effects are dependent on HA-CD44-interaction. Consequently, all utility ascribed this far to CD44-derived peptides is directly dependent on their ability to bind hyaluronic acid. Given that hyaluronic acid is widely expressed in the body at high levels, a treatment based on inhibition of this extracellular component result in a high risk for unwanted side effects outside of the tumour. Furthermore, because of the high total amounts of HA in the body, such strategy will require high doses of HA-blocking recombinant proteins, even increasing the risk for side effects. Accordingly, a need exists for finding novel drugs for treating tumours, as well as novel pathways for the relation between CD44 and tumour growth, in order to provide new drug targets, which avoid the side-effects described above. In addition, there is a need to develop novel inhibitors of angiogenesis, as these constitute potential medicaments not only for cancer, but also for an array of common diseases as disclosed above. To this end, it is important to elucidate the relation between CD44 and angiogenesis, in particular the potential direct effects of CD44 on the vasculature and on the various diseases that are dependent on new blood vessel formation. |
<SOH> SUMMARY OF THE INVENTION <EOH>Kogerman et al. [Kogerman et al., Oncogene 1997; 15: 1407-16] found that mouse fibrosarcoma cells stably expressing human CD44 standard isoform (hCD44s) had lost their hCD44s expression in large subcutaneous tumours. When hCD44s negative cells from these primary tumours were reintroduced subcutaneously into new mice for second round of tumour growth, then resulting tumours had significantly shorter latency times than hCD44s positive tumours. The observed longer latency times for hCD44s expressing tumours lead the inventors to realize that the inhibitory effect of hCD44s overexpression in subcutaneous tumour growth is connected to inhibition of tumour angiogenesis. Induction of angiogenesis is essential for growth and persistence of solid tumours and their metastases. In the absence of angiogenesis, tumours cannot grow beyond a minimal size and remain dormant in the form of micrometastases [Holmgren et al., Nat Med 1995; 1: 149-53]. The inventors have discovered here that recombinant soluble human CD44 hyaluronic acid binding (CD44HABD) domain inhibits angiogenesis in vivo in chick and endothelial cell proliferation in vitro, and thereby blocks human tumour growth in chick and mice. The inventors describe a novel type of angiogenesis inhibitor, as they found that recombinant cell surface receptor CD44 inhibits angiogenesis and tumour growth in vivo and endothelial cell proliferation in vitro. Furthermore, the inventors have created mutant forms of CD44 that are also capable of inhibiting angiogenesis. The advantage with these mutants of CD44 is that they do not bind HA, demonstrating that the mechanism for inhibition of angiogenesis is independent of binding to HA. Importantly, use of mutant CD44 for systemic administration as a medicament will be more specific for angiogenesis, since it will not be bound up by HA in the body, and can therefore be used at lower doses and has less risk of causing unwanted side effects. Accordingly, the invention refers to the use of a molecule comprising a non-HA-binding variant of the CD44-hyaluronic acid binding domain, as well as analogues and recombinant variants thereof, including the specified mutants, for the manufacturing of a medicament for treating states related to the inhibition of angiogenesis. Moreover, the invention refers to a method for screening for molecules binding to the CD44-hyaluronic acid binding domain, thereby being potential targets for inhibiting angiogenesis and for cell proliferation. Further, the invention refers to a kit for carrying out the screening method, as well as the molecules found by the method. Also, the invention refers to a molecule comprising a non-HA-binding variant of the CD44-hyaluronic acid binding domain, as well as analogues, recombinant and mutated variants thereof for targeting of endothelial cells. Hereby, drugs for treating states related to angiogenesis, such as various cancerous states, is easily provided by the invention, taking advantage of the novel mechanisms presented by the inventors. Furthermore, through the method of screening, other molecules may be found, which affect cell proliferation and/or angiogenesis. |
Process for the preparation of cilastatin |
The present invention relates to an efficient and industrially advantageous process for the preparation of pure cilastatin. |
1. A process for the purification of cilastatin which comprises contacting a solution of crude cilastatin with a non-ionic adsorbent resin and recovering pure cilastatin from a solution thereof. 2. The process of claim 1 wherein the solution of crude cilastatin is obtained directly from the reaction mixture. 3. The process of claim 1 wherein the solution of crude cilastatin is obtained by dissolving crude cilastatin in a suitable solvent. 4. The process of claim 3 wherein the suitable solvent is selected from water, an organic solvent, and mixture(s) thereof. 5. The process of claim 4 wherein the organic solvent is selected from the group consisting of methanol, ethanol, acetonitrile and acetone. 6. The process of claim 1 wherein the non-ionic adsorbent resin comprises a non-ionic macroporous water insoluble polymer. 7. The process of claim 6 wherein the polymer is selected from the group consisting of polyacrylates or copolymers of styrene and polyvinyl benzene. 8. The process of claim 7 wherein the polymer is a copolymer of styrene cross linked with divinylbenzene. 9. A process for the preparation of cilastatin comprising heating a solution of cilastatin containing the corresponding E-isomer at a pH of about 0.5 to 1.5. 10. The process of claim 9 wherein the solution is heated to 85-95° C. 11. The process of claim 9 wherein the solution is heated to 85-95° C. at a pH of about 0.5. 12. A process for the preparation of pure cilastatin comprising: (i) heating a solution of cilastatin containing the corresponding E-isomer at a pH of about 0.5 to 1.5, and (ii) contacting the solution obtained with a non-ionic adsorbent resin and recovering pure cilastatin from a solution thereof. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Cilastatin possesses the ability to prevent nephrotoxicity associated with the use of β-lactam antibiotics such as imipenem. Chemically, cilastatin is [R═{R*, S-(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[2,2-dimethylcyclopropyl)carbonyl]amino-2-heptenoic acid and has the structural Formula I. It is a renal dehydropeptidase inhibitor and is co-administered as the sodium salt with imipenem in order to prevent its renal metabolism. Imipenem/cilastatin combination is used as a potent broad spectrum antibacterial agent. Cilastatin was first disclosed in U.S. Pat. No. 5,147,868 and was obtained in a multi-step synthesis involving condensing cysteine hydrochloride with heptenoic acid of Formula II, wherein X is chloro or bromo, in the presence of sodium hydroxide in aqueous medium. Cilastatin so obtained contains the corresponding undesired E-isomer in amounts ranging from about 6 to 10% as determined by HPLC. A process for isomerising the E-isomer to cilastatin by heating the mixture at pH 3 is also disclosed. However, we have observed that the isomerization process results in the formation of impurities in the range of 5-8% due to the degradation of cilastatin which renders the product produced by this process unsuitable for human consumption. U.S. Pat. No. 5,147,868 also teaches a method for isolating cilastatin from the reaction mixture involving two purifications viz. chromatography using a cation exchange resin followed by solvent purification using ethanol and diethyl ether. The ion exchange chromatography removes inorganic salts such as sodium chloride which is otherwise difficult to remove as cilastatin itself is also water soluble. However, our attempts to isolate pure cilastatin by following the process exemplified in said patent were unsuccessful. We could obtain cilastatin in the form of its ammonium salt on eluting the cation exchange resin with ammonia solution and not as the free acid. Obtaining the free acid by using an acid such as hydrochloric acid entailed formation of inorganic ammonium salts such as ammonium chloride thus defeating the very purpose of using a cation exchange resin. J. Med. Chem. 1987; 30: 1083 discloses a process for the preparation of cilastatin involving the condensation of cysteine with the halo-heptenoic acid of Formula II in sodium metal/liquid ammonia and the resultant mixture is isomerized to obtain cilastatin using methyl iodide in methanol. Cilastatin is isolated by using a cation exchange resin followed by the treatment with an anion exchange resin to remove the inorganic salts. However, this process is not suitable on an industrial scale as it involves the use of sodium metal/liquid ammonia which are very hazardous and also uses methyl iodide for isomerization, which is expensive and requires special storage conditions. More over, loading the ion exchange column requires repeated circulation of cilastatin solution. Also, ion exchange column operates on the principle of ionic bonding/acid base reaction. Such reaction being exothermic causes considerable degradation of cilastatin. The use of two stage ion exchange chromatography is cumbersome, tedious and not practicable on an industrial scale. In light of the above drawbacks in the prior art processes, there is a need for the development of a simple, convenient and efficient process for the preparation of pure cilastatin which is convenient to operate on an industrial scale. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a process for the purification of cilastatin using a non-ionic adsorbent resin. The process requires a single purification using chromatographic technique to obtain the pure product. Loading of the non-ionic adsorbent resin with crude cilastatin is achieved by passing the solution only once through the resin. Since no acid base reaction takes place, no degradation of the product is observed. The present invention thus fulfills the need for a process which is convenient to operate on an industrial scale. Accordingly, the present invention provides a process for the purification of cilastatin which comprises contacting a solution of crude cilastatin with a non-ionic adsorbent resin and recovering pure cilastatin from a solution thereof. In the meaning of the present invention, the term “crude cilastatin” comprises cilastatin containing impurities which may be inorganic salts such as sodium chloride, sodium bromide and the like, or organic impurities which may have formed due to the degradation of cilastatin, or the side products formed during the synthesis, or unreacted intermediates of the multi-step synthesis for the preparation of cilastatin. The solution of crude cilastatin may be obtained by dissolving the crude cilastatin in a suitable solvent or may be obtained directly from the reaction mixture for the preparation of cilastatin containing already dissolved crude cilastatin. The term “suitable solvents” as used herein includes water, organic solvents, and mixtures thereof. The organic solvents include methanol, ethanol, acetonitrile, acetone, and the like. The crude cilastain may be prepared by any of the methods reported in prior art. Any of the non-ionic adsorbent resins which are commercially available and on the surface of which cilastatin is adsorbed, may be used. In particular, non-ionic macroporous water insoluble polymers such as polyacrylates or copolymers of styrene and polyvinyl benzene may be used. Preferred adsorbent resin is a copolymer of styrene cross linked with divinylbenzene. In the meaning of the present invention, the term “pure cilastatin” refers to cilastatin having a purity of 98% or more by HPLC. A typical process for the purification of cilastatin comprises loading a solution of crude cilastatin on a column of non-ionic adsorbent resin, washing it with deionized water till no halide ions can be detected. The resin is then eluted with organic or aqueous organic solvent and pure cilastatin is isolated from the eluate by common methods known in the art such as concentration, precipitation and recrystallization as required. However, alternative method of purification such as slurrying with the adsorbent resin may also be used. According to another aspect of the present invention, it provides a process for the isomerization of E-isomer to cilastatin. The process comprises heating a solution of cilastatin containing the corresponding undesired E-isomer at a pH of about 0.5 to 1.5. We have observed that cilastatin obtained using this process greatly reduces the formation of degradation products. The solution of cilastatin containing the corresponding E-isomer is preferably obtained directly from the reaction mixture for the preparation of cilastatin. Cilastatin may be prepared by any of the multi-step processes described in prior art. The isomerization is preferably performed at 85-95° C. The pH is adjusted to 0.5 to 1.5, more preferably to 0.5 to 1 and most preferably to about 0.5. Any acid may be used for adjusting the pH of the solution. Preferably, hydrochloric acid is used. In a preferred embodiment of the present invention, the two aspects of the invention are combined i.e. the isomerization process is followed by the purification process to obtain pure cilastatin. detailed-description description="Detailed Description" end="lead"? |
Functional powders for oral delivery |
In certain embodiments the invention is directed to a drug formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient, said core overcoated with a functional coating, said drug particles having a mean diameter of greater than 10 μm to about 1 mm. |
1. A drug formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient, said core overcoated with a functional coating, said drug particles having a mean diameter of greater than 10 μm to about 1 mm, said particles comprising at least about 40% drug. 2. The drug formulation of claim 1 wherein said core comprises drug coated with said excipient and said functional coat overcoats the excipient coat. 3. The drug formulation of claim 1 wherein said core comprises a drug interdispersed in said excipient. 4. The formulation of claim 3 wherein said drug and said excipient are wet granulated. 5. The formulation of claim 3 wherein said drug and said excipient are melt granulated. 6. The formulation of claim 3 wherein said drug and a first portion of said excipient are wet granulated and the resultant wet granulated particles are melt granulated with a second portion of said excipient. 7. The formulation of claim 6 wherein said first portion of excipient and said second portion of excipient comprise the same material. 8. The formulation of claim 6 wherein said first portion of excipient and said second portion of excipient comprise different materials. 9. The formulation of claim 1 wherein said functional coated particles are melt granulated with a pharmaceutically acceptable excipient. 10. The formulation of claim 5 wherein a difference between a film forming temperature of the melt granulating excipient and the film forming temperature of the functional coat is more than 15 degrees C. 11. The formulation of claim 10 wherein the difference between a film forming temperature of a melt granulating excipient and the film forming temperature of a functional coat is more than 20 degrees C. 12. The formulation of claim 11 wherein a difference between a film forming temperature of the melt granulating excipient and a film forming temperature of the functional coat is more than 25 degrees C. 13. The formulation of claim 5 wherein the melt granulating excipient is selected from the group consisting of beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, cetyl alcohol, stearyl alcohol, stearic acid; esters of wax acids; propylene glycol monostearate, glyceryl monostearate; carnauba wax, glyceryl palmitostearate, glyceryl behenate, polyethylene glycol, and a combination thereof. 14. The drug formulation of claim 1 wherein said excipient provides a controlled release of the drug upon gastrointestinal deposition. 15. The drug formulation of claim 14 wherein said excipient provides a controlled release of the drug upon gastrointestinal deposition to provide a therapeutic effect for at least 12 hours after oral administration. 16. The drug formulation of claim 14 wherein said excipient provides a controlled release of the drug upon gastrointestinal deposition to provide a therapeutic effect for at least 24 hours after oral administration. 17. The drug formulation of claim 1 wherein said excipient provides a delayed release of the drug upon gastrointestinal deposition. 18. The drug formulation of claim 17 wherein said excipient provides a delayed release of the drug upon gastrointestinal deposition to effect intestinal absorption. 19. The drug formulation of claim 1 wherein said excipient provides tastemasking. 20. The drug formulation of claim 1 wherein said excipient comprises a salivary stimulant. 21. The drug formulation of claim 2 wherein said excipient provides a moisture barrier. 22. The drug formulation of claim 1 wherein said excipient provides a texture modifier. 23. The drug formulation of claim 1 wherein said functional coating provides a controlled release of the drug upon gastrointestinal deposition. 24. The drug formulation of claim 12 wherein said functional coating provides a controlled release of the drug upon gastrointestinal deposition to provide a therapeutic effect for at least 12 hours after oral administration. 25. The drug formulation of claim 12 wherein said functional coating provides a controlled release of the drug upon gastrointestinal deposition to provide a therapeutic effect for at least 24 hours after oral administration. 26. The drug formulation of claim 1 wherein said functional coating provides a delayed release of the drug upon gastrointestinal deposition. 27. The drug formulation of claim 26 wherein said functional coating provides a delayed release of the drug upon gastrointestinal deposition to effect intestinal absorption. 28. The drug formulation of claim 1 wherein said functional coating provides tastemasking. 29. The drug formulation of claim 1 wherein said functional coating comprises a salivary stimulant. 30. The drug formulation of claim 1 wherein said functional coating provides a moisture barrier. 31. The drug formulation of claim 1 wherein said functional coating provides a texture modifier. 32. The drug formulation of claim 1 wherein said functional coating minimizes asperities on the surface of said particles. 33. The drug formulation of claim 1 wherein said functional coating is resistant to chipping. 34. The drug formulation of claim 1 wherein said functional coating provides pliability to said particles. 35. The drug formulation of claim 1 wherein said drug particles have a mean diameter of greater than about 50 μm. 36. The drug formulation of claim 1 wherein greater than 90% of said particles have a diameter of greater than about 10 μm. 37. The drug formulation of claim 1 wherein greater than 95% of said particles have a diameter of greater than about 10 μm. 38. The drug formulation of claim 1 wherein greater than 99% of said particles have a diameter of greater than about 10 μm. 39. The drug formulation of claim 1 wherein greater than 90% of said particles have a diameter of greater than about 50 μm. 40. The drug formulation of claim 1 wherein greater than 95% of said particles have a diameter of greater than about 50 μm. 41. The drug formulation of claim 1 wherein greater than 99% of said particles have a diameter of greater than about 50 μm. 42. The drug formulation of claim 14 wherein said controlled release excipient is a hydrophobic material. 43. The drug formulation of claim 42 wherein said hydrophobic material is selected from the group consisting of an acrylic polymer, a cellulosic material, shellac, zein and mixtures thereof. 44. The drug formulation of claim 42 wherein said hydrophobic material is an acrylic polymer. 45. The drug formulation of claim 44 wherein said acrylic polymer is selected from the group consisting of acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid, methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers and mixtures thereof. 46. The drug formulation of claim 42 wherein said controlled release excipient is a cellulosic material. 47. The drug formulation of claim 46 wherein said cellulosic material is selected from the group consisting of cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate and mixtures thereof. 48. The drug formulation of claim 17 wherein said delayed release material is an enteric polymer. 49. The drug formulation of claim 37 wherein said enteric polymer is selected from the group consisting of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose and mixtures thereof. 50. The drug formulation of claim 19 wherein said tastemasking material is selected from the group consisting of water-soluble sweetening agents, water-soluble artificial sweeteners, dipeptide based sweeteners and mixtures thereof. 51. The drug formulation of claim 50 wherein said water-soluble sweetening agent is selected from the group consisting of monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrup solids and sugar alcohols such as sorbitol, xylitol, or mannitol and mixtures thereof. 52. The drug formulation of claim 50 wherein said water-soluble artificial sweetener is selected from the group consisting of soluble saccharin salts, such as sodium or calcium saccharin salts, cyclamate salts, acesulfam-K, the free acid form of saccharin and mixtures thereof. 53. The drug formulation of claim 50 wherein said dipeptide based sweetener is L-aspartyl L-phenylalanine methyl ester. 54. The drug formulation of claim 20 wherein said salivary stimulant is selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides thereof, acid salts thereof and combinations thereof. 55. The drug formulation of claim 21 wherein said moisture barrier material is selected from the group consisting of acacia gum, acrylic acid polymers and copolymers (polyacrylamides, polyacryldextrans, polyalkyl cyanoacrylates, polymethyl methacrylates), agar-agar, agarose, albumin, alginic acid and alginates, carboxyvinyl polymers, cellulose derivatives such as cellulose acetate, polyamides (nylon 6-10, poly(adipyl-L-lysines, polyterephthalamides and poly-(terephthaloyl-L-lysines)), poly-.epsilon.-caprolactam, polydimethylsiloxane, polyesters, poly(ethylene-vinyl acetate), polyglycolic acid, polyactic acid and its copolymers, polyglutamic acid, polylysine, polystyrene, shellac, xanthan gum, anionic polymers of methacrylic acid and methacrylic acid esters, hydroxyalkylcelluloses and mixtures thereof. 56. The drug formulation of claim 55 wherein said hydroxyalkylcellulose is hydroxypropylmethylcellulose. 57. The drug formulation of claim 22 wherein said texture modifier is selected from the group consisting of acacia gum, acrylic acid polymers and copolymers (polyacrylamides, polyacryldextrans, polyalkyl cyanoacrylates, polymethyl methacrylates), agar-agar, agarose, albumin, alginic acid and alginates, carboxyvinyl polymers, cellulose derivatives such as cellulose acetate, polyamides (nylon 6-10, poly(adipyl-L-lysines, polyterephthalamides and poly-(terephthaloyl-L-lysines)), poly-epsilon.-caprolactam, polydimethylsiloxane, polyesters, poly (ethylene-vinyl acetate), polyglycolic acid, polyactic acid and its copolymers, polyglutamic acid, polylysine, polystyrene, shellac, xanthan gum, anionic polymers of methacrylic acid and methacrylic acid esters, hydroxyalkylcelluloses and mixtures thereof. 58. The drug formulation of claim 32 wherein said particulates have a mean rugosity of from about 1.0 to about 1.5. 59. The drug formulation of claim 33 wherein said chip resistant coating comprises a material selected from the group consisting of acacia gum, alginic acid and alginates, carboxymethylcellulose, ethylcellulose, gelatine, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, xanthan gum, pectin, tragacanth, microcrystalline cellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, gum arabic, lactose, starch (wheat, maize, potato and rice starch), sucrose, glucose, mannitol, sorbitol, xylitol, stearic acid, hydrogenated cottonseed oil, hydrogenated castor oil, vinylpyrrolidone-vinyl acetate copolymers, fructose, methylhydroxyethylcellulose, agar-agar, carrageenan, karaya gum, chitosan, starch hydrolysates and mixtures thereof. 60. The drug formulation of claim 34 wherein said pliable coating comprises a plasticizer selected from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl citrate, triacetin and mixtures thereof. 61. A drug delivery system comprising a dosing device comprising a housing and an actuator, said device containing at least one unit dose of a drug formulation according to claim 1, said device upon actuation delivering a unit dose of said drug formulation such that an effective dose of said drug cannot be delivered into the lower lung of a human patient. 62. A drug delivery system comprising a multiple unit dosing device comprising a housing and an actuator, said device containing multiple unit doses of a drug formulation according to claim 1, said device upon actuation delivering a unit dose of said drug formulation such that an effective dose of said drug cannot be delivered into the lower lung of a human patient. 63. A drug delivery system comprising a multiple unit dosing device comprising a housing and an actuator, said device containing at least one unit dose of a drug formulation comprising a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient, said core overcoated with a functional coating, said drug particles having a mean diameter of greater than 10 μm to about 1 mm, said device upon actuation delivering a unit dose of said drug formulation such that an effective dose of said drug cannot be delivered into the lower lung of a human patient. 64. The formulation of claim 63 wherein said drug and said excipient are wet granulated. 65. The formulation of claim 63 wherein said drug and said excipient are melt granulated. 66. The formulation of claim 63 wherein said drug and a first portion of said excipient are wet granulated and the resultant wet granulated particles are melt granulated with a second portion of said excipient. 67. The formulation of claim 66 wherein said first portion of excipient and said second portion of excipient comprise the same material. 68. The formulation of claim 66 wherein said first portion of excipient and said second portion of excipient comprise different materials. 69. The formulation of claim 63 wherein said functional coated particles are melt granulated with a pharmaceutically acceptable excipient. 70. The formulation of claim 65 wherein a difference between a film forming temperature of the melt granulating excipient and a film forming temperature of a functional coat is more than 15 degrees C. 71. The formulation of claim 70 wherein a difference between a film forming temperature of a melt granulating excipient and a film forming temperature of the functional coat is more than 20 degrees C. 72. The formulation of claim 71 wherein a difference between a film forming temperature point of the melt granulating excipient and a film forming temperature of the functional coat is more than 25 degrees C. 73. The formulation of claim 65 wherein the melt granulating excipient is selected from the group consisting of beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, cetyl alcohol, stearyl alcohol, stearic acid; esters of wax acids; propylene glycol monostearate, glyceryl monostearate; carnauba wax, glyceryl palmitostearate, glyceryl behenate, polyethylene glycol, and a combination thereof. 74. A method of administering a drug to a human patient for gastrointestinal deposition comprising formulating a drug formulation comprising a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient, said core overcoated with a functional coating, said drug particles having a mean diameter of greater than 10 μm to about 1 mm, containing said drug formulation in a drug delivery device capable of administering multiple unit doses of said multiparticulates into the oral cavity; administering a unit dose of the multiparticulates to the oral cavity wherein greater than about 80% of the unit dose is deposited in the gastrointestinal tract. 75. A method of preparing a drug delivery system for delivering multiple doses of a drug for gastrointestinal deposition comprising preparing a drug formulation comprising a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient, said core overcoated with a functional coating, said drug particles having a mean diameter of greater than 10 μm to about 1 mm; and placing multiple unit doses of said drug formulation in a device which meters a single unit dose for delivery. 76. The method of claim 74 wherein said core comprises drug coated with said excipient and said functional coat overcoats the excipient coat. 77. The method of claim 74 wherein said core comprises a drug interdispersed in said excipient. 78. The formulation of claim 77 wherein said drug and said excipient are wet granulated. 79. The formulation of claim 77 wherein said drug and said excipient are melt granulated. 80. The formulation of claim 77 wherein said drug and a first portion of said excipient are wet granulated and the resultant wet granulated particles are melt granulated with a second portion of said excipient. 81. The formulation of claim 80 wherein said first portion of excipient and said second portion of excipient comprise the same material. 82. The formulation of claim 80 wherein said first portion of excipient and said second portion of excipient comprise different materials. 83. The formulation of claim 74 wherein said functional coated particles are melt granulated with a pharmaceutically acceptable excipient. 84. The formulation of claim 79 wherein a difference between a film forming temperature of the melt granulating excipient and a film forming temperature of the functional coat is more than 15 degrees C. 85. The formulation of claim 84 wherein a difference between a film forming temperature of the melt granulating excipient and a film forming temperature of the functional coat is more than 20 degrees C. 86. The formulation of claim 85 wherein a difference between a film forming temperature of the melt granulating excipient and a film forming temperature of the functional coat is more than 25 degrees C. 87. The formulation of claim 79 wherein the melt granulating excipient is selected from the group consisting of beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, cetyl alcohol, stearyl alcohol, stearic acid; esters of wax acids; propylene glycol monostearate, glyceryl monostearate; carnauba wax, glyceryl palmitostearate, glyceryl behenate, polyethylene glycol, and a combination thereof. 88. The method of claim 74 wherein said excipient provides a controlled release of the drug upon gastrointestinal deposition. 89. The method of claim 88 wherein said excipient provides a controlled release of the drug upon gastrointestinal deposition to provide a therapeutic effect for at least 12 hours after oral administration. 90. The method of claim 88 wherein said excipient provides a controlled release of the drug upon gastrointestinal deposition to provide a therapeutic effect for at least 24 hours after oral administration. 91. The method of claim 74 wherein said excipient provides a delayed release of the drug upon gastrointestinal deposition. 92. The method of claim 91 wherein said excipient provides a delayed release of the drug upon gastrointestinal deposition to effect intestinal absorption. 93. The method of claim 74 wherein said excipient provides tastemasking. 94. The method of claim 74 wherein said excipient comprises a salivary stimulant. 95. The method of claim 76 wherein said excipient provides a moisture barrier. 96. The method of claim 74 wherein said excipient provides a texture modifier. 97. The method of claim 74 wherein said functional coating provides a controlled release of the drug upon gastrointestinal deposition. 98. The method of claim 97 wherein said functional coating provides a controlled release of the drug upon gastrointestinal deposition to provide a therapeutic effect for at least 12 hours after oral administration. 99. The method of claim 97 wherein said functional coating provides a controlled release of the drug upon gastrointestinal deposition to provide a therapeutic effect for at least 24 hours after oral administration. 100. The method of claim 74 wherein said functional coating provides a delayed release of the drug upon gastrointestinal deposition. 101. The method of claim 100 wherein said functional coating provides a delayed release of the drug upon gastrointestinal deposition to effect intestinal absorption. 102. The method of claim 74 wherein said functional coating provides tastemasking. 103. The method of claim 74 wherein said functional coating comprises a salivary stimulant. 104. The method of claim 74 wherein said functional coating provides a moisture barrier. 105. The method of claim 74 wherein said functional coating provides a texture modifier. 106. The method of claim 74 wherein said functional coating minimizes asperities on the surface of said particles. 107. The method of claim 74 wherein said functional coating is resistant to chipping. 108. The method of claim 74 wherein said functional coating provides pliability to said particles. 109. The system of claim 74 wherein said drug particles have a mean diameter of greater than about 50 μm. 110. The method of claim 74 wherein greater than 90% of said particles have a diameter of greater than about 10 μm. 111. The method of claim 74 wherein greater than 95% of said particles have a diameter of greater than about 10 μm. 112. The method of claim 74 wherein greater than 99% of said particles have a diameter of greater than about 10 μm. 113. The method of claim 74 wherein greater than 90% of said particles have a diameter of greater than about 50 μm. 114. The method of claim 74 wherein greater than 95% of said particles have a diameter of greater than about 50 μm. 115. The method of claim 74 wherein greater than 99% of said particles have a diameter of greater than about 50 μm. 116. The method of claim 88 wherein said controlled release excipient is a hydrophobic material. 117. The method of claim 116 wherein said hydrophobic material is selected from the group consisting of an acrylic polymer, a cellulosic material, shellac, zein and mixtures thereof. 118. The method of claim 116 wherein said hydrophobic material is an acrylic polymer. 119. The method of claim 118 wherein said acrylic polymer is selected from the group consisting of acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, methyl methacrylate, copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methyl methacrylate copolymers, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymers, methyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid, methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers and mixtures thereof. 120. The method of claim 116 wherein said controlled release excipient is a cellulosic material. 121. The method of claim 120 wherein said cellulosic material is selected from the group consisting of cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate and mixtures thereof. 122. The method of claims 91 and 100 wherein said delayed release material is an enteric polymer. 123. The method of claim 122 wherein said enteric polymer is selected from the group consisting of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose and mixtures thereof. 124. The method of claim 93 wherein said tastemasking material is selected from the group consisting of water-soluble sweetening agents, water-soluble artificial sweeteners, dipeptide based sweeteners and mixtures thereof. 125. The drug formulation of claim 124 wherein said water-soluble sweetening agent is selected from the group consisting of monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzed starch, or corn syrup solids and sugar alcohols such as sorbitol, xylitol, or mannitol and mixtures thereof. 126. The method of claim 124 wherein said water-soluble artificial sweetener is selected from the group consisting of soluble saccharin salts, such as sodium or calcium saccharin salts, cyclamate salts, acesulfam-K, the free acid form of saccharin and mixtures thereof. 127. The method of claim 124 wherein said dipeptide based sweetener is L-aspartyl L-phenylalanine methyl ester. 128. The method of claim 94 wherein said salivary stimulant is selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides thereof, acid salts thereof and combinations thereof. 129. The method of claim 95 wherein said moisture barrier material is selected from the group consisting of acacia gum, acrylic acid polymers and copolymers (polyacrylamides, polyacryldextrans, polyalkyl cyanoacrylates, polymethyl methacrylates), agar-agar, agarose, albumin, alginic acid and alginates, carboxyvinyl polymers, cellulose derivatives such as cellulose acetate, polyamides (nylon 6-10, poly(adipyl-L-lysines, polyterephthalamides and poly-(terephthaloyl-L-lysines)), poly-.epsilon.-caprolactam, polydimethylsiloxane, polyesters, poly (ethylene-vinyl acetate), polyglycolic acid, polyactic acid and its copolymers, polyglutamic acid, polylysine, polystyrene, shellac, xanthan gum, anionic polymers of methacrylic acid and methacrylic acid esters, hydroxyalkylcelluloses and mixtures thereof. 130. The method of claim 129 wherein said hydroxyalkylcellulose is hydroxypropylmethylcellulose. 131. The method of claim 96 wherein said texture modifier is selected from the group consisting of acacia gum, acrylic acid polymers and copolymers (polyacrylamides, polyacryldextrans, polyalkyl cyanoacrylates, polymethyl methacrylates), agar-agar, agarose, albumin, alginic acid and alginates, carboxyvinyl polymers, cellulose derivatives such as cellulose acetate, polyamides (nylon 6-10, poly(adipyl-L-lysines, polyterephthalamides and poly-(terephthaloyl-L-lysines)), poly-.epsilon.-caprolactam, polydimethylsiloxane, polyesters, poly (ethylene-vinyl acetate), polyglycolic acid, polyactic acid and its copolymers, polyglutamic acid, polylysine, polystyrene, shellac, xanthan gum, anionic polymers of methacrylic acid and methacrylic acid esters, hydroxyalkylcelluloses and mixtures thereof. 132. The method of claim 116 wherein said particulates have a mean rugosity of from about 1.0 to about 1.5. 133. The drug formulation of claim 77 wherein said chip resistant coating comprises a material selected from the group consisting of acacia gum, alginic acid and alginates, carboxymethylcellulose, ethylcellulose, gelatine, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, xanthan gum, pectin, tragacanth, microcrystalline cellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycols, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, gum arabic, lactose, starch (wheat, maize, potato and rice starch), sucrose, glucose, mannitol, sorbitol, xylitol, stearic acid, hydrogenated cottonseed oil, hydrogenated castor oil, vinylpyrrolidone-vinyl acetate copolymers, fructose, methylhydroxyethylcellulose, agar-agar, carrageenan, karaya gum, chitosan, starch hydrolysates and mixtures thereof. 134. The method of claim 108 wherein said pliable coating comprises a plasticizer selected from the group consisting of dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl citrate, triacetin and mixtures thereof. 135. A method of preparing a multiparticulate drug formulation for gastrointestinal deposition with minimal potential for surface water coalesence comprising preparing a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient, and overcoating said core with a coating minimizes water coalesence on the surface of said particles. 136. A method of preparing a multiparticulate drug formulation for gastrointestinal deposition with minimal static charge comprising preparing a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient, and overcoating said core with a coating which minimizes static charge between said particles. 137. A method of preparing a multiparticulate drug formulation for gastrointestinal deposition comprising preparing a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient air jet sieving said particles to separate said cores from fine particles; and overcoating said core with a functional coating. 138. A method of preparing a multiparticulate drug formulation with improved weight uniformity for gastrointestinal deposition comprising preparing a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient; and overcoating said core with a functional coating. 139. A method of preparing a multiparticulate drug formulation for gastrointestinal deposition with minimal change in cohesiveness in response to humidity change comprising preparing a non-compressed free flowing plurality of particles comprising a core comprising a drug and a pharmaceutically acceptable excipient; and overcoating said core with a functional coating such that the cohesiveness of said particles does not substantially change over a humidity gradient from about 10% relative humidity to about 90% relative humidity. 140. The method of claim 137 wherein said fine particles are less than about 50 micrometers. 141. The method of claim 137 wherein said fine particles are less than about 25 micrometers. 142. The method of claim 137 wherein said fine particles are less than about 10 micrometers. 143. The method of claim 137 further comprising filtering said particles prior to air jet sieving to remove particles greater than about 500 micrometers. 144. The method of claim 143 further comprising filtering said particles prior to air jet sieving to remove particles greater than about 750 micrometers. 145. The method of claim 144 further comprising filtering said particles prior to air jet sieving to remove particles greater than about 1 mm. 146. The method of claim 135 comprising preparing said particles with an amount of coloring agents which minimizes weakening of the adhesion of the overcoat to the core. 147. The method of claim 146 wherein said coloring agent is selected from the group consisting of a lake, an opacifier or a combination thereof. 148. The method of claim 146 wherein said coloring agent does not comprise a lake. 149. The method of claim 146 wherein said coloring agent does not comprise an opacifier. 150. The method of claim 146 wherein said coloring agent does not comprise a lake or an opacifier. 151. The method of claim 135 wherein said overcoat comprises a plasticizer. 152. The method of claim 139 wherein the cohesiveness of said particles does not substantially change over a humidity gradient from about 20% relative humidity to about 80% relative humidity. 153. The method of claim 152 wherein the cohesiveness of said particles does not substantially change over a humidity gradient from about 40% relative humidity to about 60% relative humidity. 154. The method of claim 137 wherein said overcoat comprises a conductive polymer. 155. The method of claim 135 wherein said drug particles having a mean diameter of greater than 10 μm to about 1 mm. 156. The method of claim 155 wherein said drug particles having a mean diameter of greater than 50 μm to about 500 μm. 157. The method of claim 135 wherein said particles comprise at least about 40%, at least about 50%, at least about 60%, at least about 70% or at least about 80% drug. 158. The method of claim 135 wherein said core comprises drug coated with said excipient and said functional coat overcoats the excipient coat. 159. The method of claim 135 wherein said core comprises a drug interdispersed in said excipient. 160. The method of claim 159 wherein said drug and said excipient are wet granulated. 161. The method of claim 159 wherein said drug and said excipient are melt granulated. 162. The method of claim 159 wherein said drug and a first portion of said excipient are wet granulated and the resultant wet granulated particles are melt granulated with a second portion of said excipient. 163. The method of claim 162 wherein said first portion of excipient and said second portion of excipient comprise the same material. 164. The method of claim 162 wherein said first portion of excipient and said second portion of excipient comprise different materials. 165. The method of claim 135 wherein said functional coated particles are melt granulated with a pharmaceutically acceptable excipient. 166. The method of claim 161 wherein a difference between a film forming temperature of the melt granulating excipient and a film forming temperature of the functional coat is more than 15 degrees C. 167. The method of claim 166 wherein a difference between a film forming temperature of the melt granulating excipient and a film forming temperature of the functional coat is more than 20 degrees C. 168. The method of claim 166 wherein a difference between a film forming temperature of a melt granulating excipient and a film forming temperature of the functional coat is more than 25 degrees C. 169. The method of claim 161 wherein the melt granulating excipient is selected from the group consisting of beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, cetyl alcohol, stearyl alcohol, stearic acid; esters of wax acids; propylene glycol monostearate, glyceryl monostearate; carnauba wax, glyceryl palmitostearate, glyceryl behenate, polyethylene glycol, and a combination thereof. 170. A multiparticulate formulation obtained according to a process of claim 135. 171. A controlled release formulation comprising a drug and a sufficient amount of a lacquer agent to provide a controlled release of the drug. 172. The formulation of claim 171 wherein said lacquer agent is selected from the group consisting of corn oil, cottonseed oil, menhaden oil, pine oil, peanut oil, safflower oil, sesame oil, soybean oil, linseed oil and mixtures thereof. 173. The formulation of claim 171 wherein said lacquer agent is selected from the group consisting of fatty acids of C8-C20 oils which can be saturated, unsaturated, glycerides thereof, and combination thereof. 174. The formulation of claim 171 wherein said lacquer agent is selected from the group consisting of branched or polycarboxylated oils such as linoleic acid, linolenic acid, oleic acid and combinations thereof. 175. The formulation of claim 171 wherein said lacquer agent is selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, lignoceric acid and combinations thereof. 176. The formulation of claim 171 wherein said lacquer agent is at least partially interdispersed with said drug. 177. The formulation of claim 171 wherein said lacquer agent is coated onto said drug. 178. The formulation of claim 171 wherein said formulation is in multiparticulate form. 179. The formulation of claim 171 wherein said formulation is a tablet. 180. The formulation of claim 171 further comprising a channeling agent such as polyvinylpyrrolidone, polyethyleneglycols, dextrose, sucrose, mannitol, xylitol, lactose and combinations thereof. 181. The formulation of claim 171 further comprising a dispersing agent such as colloidal silicone dioxide, talc, kaolin, silicone dioxide, colloidal calcium carbonate, bentonite, Fuller's earth, magnesium aluminum silicate and mixtures thereof. 182. A method of preparing a multiparticulate drug formulation for gastrointestinal deposition comprising preparing a non-compressed free flowing plurality of particles comprising a drug and air jet sieving said particles to separate fine particles. 183. The method of claim 182 wherein said fine particles are less than about 50 micrometers. 184. The method of claim 182 wherein said fine particles are less than about 25 micrometers. 185. The method of claim 182 wherein said fine particles are less than about 10 micrometers. 186. The method of claim 182 further comprising filtering said particles prior to air jet sieving to remove particles greater than about 500 micrometers. 187. The method of claim 182 further comprising filtering said particles prior to air jet sieving to remove particles greater than about 750 micrometers. 188. The method of claim 182 further comprising filtering said particles prior to air jet sieving to remove particles greater than about 1 mm. 189. The method of claim 182 further comprising placing a plurality of said multiparticulates in a dosing device capable of metering a unit dose of said formulation for oral delivery. 190. A composition obtained from a method of claim 182. 191. A formulation for gastrointestinal deposition comprising a non-compressed free flowing plurality of particles comprising a core comprising chlorpheniramine or a salt thereof and a pharmaceutically acceptable excipient, said core overcoated with a functional coating, said particles having a mean diameter of greater than 10 μm to about 1 mm. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The most prominent mode of delivery of therapeutic agents is by the oral route by means of solid dosage forms such as tablets and capsules. Oral administration of solid dosage forms is more convenient and accepted than other modes of administration, e.g. parenteral administration. However, the manufacture, dispensing and administration of solid dosage forms are not without associated problems and drawbacks. With the manufacture of solid dosage forms, in addition to the active agent, it is necessary to combine other ingredients in the formulations for various reasons, such as to enhance physical appearance, to provide necessary bulk for tableting or capsuling, to improve stability, to improve compressibility or to aid in disintegration after administration. However, these added excipients have been shown to adversely influence the release, stability and bioavailability of the active ingredient. The added excipients are a particular problem with drugs which require a high dose in order to provide a therapeutic effect, e.g., biphosphonate drugs. The inclusion of the additional excipient can make the final tablet extremely large which could result in esophogeal damage due to the physical characteristics of the dosage form if it is not swallowed properly. Esophogeal damage can also be caused by toxicity caused by the drug itself, if the tablet becomes lodged in the throat or has an increased transit time through the esophagus, due to its increased size. Further, the tableting of certain drugs has many associated production problems. In particular, many drugs, e.g., acetaminophen, have poor compressibility and cannot be directly compressed into solid dosage forms. Consequently, such drugs must either be wet granulated or manufactured in a special grade in order to be tableted which increases manufacturing steps and production costs. The adherence to good manufacturing practices and process controls is essential in order to minimize dosage form to dosage form and batch to batch variations of the final product. Even strict adherence to these practices still is not a guarantee that acceptable variation will occur. With the high cost of industrial scale production and governmental approval of solid dosage forms, such formulations are often available in a limited number of strengths, which only meet the needs of the largest sectors of the population. Unfortunately, this practice leaves many patients without acceptable means of treatment and physicians in a quandary with respect to individualizing dosages to meet the clinical needs of their patients. The dispensing of oral solid dosage forms also makes the formulations susceptible to degradation and contamination due to repackaging, improper storage and manual handling. There are also many patients who are unable or unwilling to take conventional orally administered dosage forms. For some patients, the perception of unacceptable taste or mouth feel of a dose of medicine leads to a gag reflex action that makes swallowing difficult or impossible. Other patients, e.g., pediatric and geriatric patients, find it difficult to ingest typical solid oral dosage forms, e.g., due to tablet size. Other patients, particularly elderly patients, have conditions such as achlorhydria which hinders the successful use of oral solid dosage forms. Achlorhydria is a condition wherein there is an abnormal deficiency or absence of free hydrochloric acid in the gastric secretions of the stomach. This condition hinders the disintegration and/or dissolution of oral solid dosage forms, particularly dosage forms with high or insoluble excipient payloads. Thus, as the present dosage form is in multiparticulate form, it does need to undergo disintegration and/or dissolution to the same extent as solid dosage forms. Flavored solutions/suspensions of some therapeutic agents have been developed to facilitate the oral administration of oral agents to patients normally having difficulty ingesting conventional solid oral dosage forms. While liquid formulations are more easily administered to the problem patient, liquid/suspension formulations are not without their own significant problems and restrictions. The liquid dose amount is not as easily controlled compared with tablet and capsule forms and many therapeutic agents are not sufficiently stable in solution/suspension form. Indeed, most suspension type formulations are typically reconstituted by the pharmacist and then have a limited shelf life even under refrigerated conditions. Another problem with liquid formulations which is not as much a factor with tablets and capsules is the taste of the active agent. The taste of some therapeutic agents is so unacceptable that liquid formulations are not a viable option. Further, solution/suspension type formulations are typically not acceptable where the active agent must be provided with a protective coating, e.g. a taste masking coating or an enteric coating to protect the active agent from the strongly acidic conditions of the stomach. Due to the disadvantages of known drug delivery discussed above (as well as other disadvantages) there exists a need in the art for the development of a multiparticulate formulation for facilitating delivery of a wide range of therapeutic agents for gastrointestinal deposition and which minimize pulmonary deposition of materials having undesirable or unknown pulmonary toxicology but which are approved for oral delivery. In preferred embodiments, the formulation contains minimal excipient and is used in a multiple dose delivery device which dispenses a unit dose of the powder upon actuation. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a graph of adhesion vs. humidity for standard powders. FIG. 2 is a graph of adhesion vs. humidity for powders of the present invention. FIG. 3 is a dissolution profile of Indomethacin & 4% PVP K-30 wet granulation in a pH 6.8 phosphate buffer made in accordance with an embodiment of the present invention. FIG. 4 is a pH 6.8 phosphate buffer dissolution profile of Indomethacin & 10% PEG6000 melt granulation made in accordance with an embodiment of the present invention. FIG. 5 is a 0.1 N Hydrochloric Acid dissolution profile of Indomethacin & 10% PEG6000 & 15% Acryl-eze melt granulation made in accordance with an embodiment of the present invention. FIG. 6 is a pH 6.8 phosphate buffer dissolution profile of Indomethacin & 10% PEG6000 & 15% Acryl-eze melt granulation made in accordance with an embodiment of the present invention. FIG. 7 is a 0.1 N Hydrochloric Acid dissolution profile of Indomethacin & 15% Sureteric & 10% PEG6000 melt granulation made in accordance with an embodiment of the present invention. FIG. 8 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin & 15% Sureteric & 10% PEG6000 melt granulation made in accordance with an embodiment of the present invention. FIG. 9 is a 0.1 N Hydrochloric Acid dissolution profile of Indomethacin & 15% Sureteric melt granulation made in accordance with an embodiment of the present invention. FIG. 10 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin & 15% Sureteric melt granulation made in accordance with an embodiment of the present invention. FIG. 11 is a 0.1 N Hydrochloric Acid dissolution profile of Indomethacin & 15% Sureteric & 10% Lustre Clear melt granulation made in accordance with an embodiment of the present invention. FIG. 12 is a 6.8 pH phosphate buffer dissolution profile of Indomethacin & 15% Sureteric & 10% Lustre Clear melt granulation made in accordance with an embodiment of the present invention. FIG. 13 depicts the particle size distribution for the formulations made in accordance with an embodiment of the present invention. detailed-description description="Detailed Description" end="lead"? |
Apparatus and method for generating a code mask |
A new output mask for a m-sequence generator is produced by modulo-2 summing a number of intermediate masks. The intermediate masks are produced by shifting a shift template by amounts corresponding to offsets of set bits in an existing output mask. If an intermediate mask contains set bits beyond its portion corresponding to the new output mask, then they are wrapped back. |
1. A method of creating a new output mask for a m-sequence generator, comprising creating an intermediate mask for each bit set in an existing output mask and performing modulo-2 summation on all the intermediate masks produced to create the new output mask, wherein each intermediate mask is created by shifting a shift template by an offset equal to the offset of the corresponding set bit in the existing output mask. 2. A method according to claim 1, wherein each intermediate mask comprises an aligned portion aligned with the new output mask and the new output mask is produced through modulo-2 summation of all the aligned portions. 3. A method according to claim 2, wherein if an intermediate mask has beyond its aligned portion an excess portion containing one or more set bits, then said one or more excess portion set bits are used to influence the effect of the intermediate mask on the new output mask. 4. A method according to claim 3, wherein said one or more excess portion set bits are used to adjust the new output mask after their intermediate mask has taken part in said summation. 5. A method according to claim 3, wherein said one or more excess portion set bits are used to adjust the new output mask at the same time as their intermediate mask takes part in said summation. 6. A method according to claim 3, wherein said one or more excess portion set bits are used to adjust their intermediate mask before it takes part in said summation. 7. A method according to claim 3, wherein the influence of said one or more excess portion set bits is determined by the nature of a feedback arrangement in the generator. 8. Apparatus for creating a new output mask for a m-sequence generator comprising a calculator for creating an intermediate mask for each bit set in an existing output mask and a combiner for performing modulo-2 summation on all the intermediate masks produced to create the new output mask, wherein the calculator produces each intermediate mask by shifting a shift template by an offset equal to the offset of the corresponding set bit in the existing output mask. 9. Apparatus according to claim 8, wherein each intermediate mask comprises an aligned portion aligned with the new output mask and the combiner is arranged to produce the new output mask through modulo-2 summation of all the aligned portions. 10. Apparatus according to claim 9, wherein, where an intermediate mask has beyond its aligned portion an excess portion containing one or more set bits, the combiner is arranged to use said one or more excess portion set bits to influence the effect of the intermediate mask on the new output mask. 11. Apparatus according to claim 10, wherein the combiner is arranged to use said one or more excess portion set bits to adjust the new output mask after their intermediate mask has taken part in said summation. 12. Apparatus according to claim 10, wherein the combiner is arranged to use said one or more excess portion set bits to adjust the new output mask at the same time as their intermediate mask takes part in said summation. 13. Apparatus according to claim 10, wherein the combiner is arranged to use said one or more excess portion set bits to adjust their intermediate mask before it takes part in said summation. 14. Apparatus according to claim 10, wherein the combiner is arranged to influence the new output mask with said one or more excess portion set bits in a manner determined by the nature of a feedback arrangement of the generator. 15. A computer readable medium containing computer-executable instructions for causing data processing apparatus to perform a method of creating a new output mask for a m-sequence generator, the method comprising creating an intermediate mask for each bit set in an existing output mask and performing modulo-2 summation on all the intermediate masks produced to create the new output mask, wherein each intermediate mask is created by shifting a shift template by an offset equal to the offset of the corresponding set bit in the existing output mask. 16. Canceled 17. Canceled |
Color-changing material composition and color-changing membranes made by using the same |
A color-changing material composition which comprises a binder resin comprising a copolymer of a methacrylic ester and methacrylic acid having a specific structure (Component A), at least one fluorescent coloring matter (Component B) and a monomer and/or oligomer having a photopolymerizable ethylenically unsaturated group (Component C) and color-changing membranes formed by curing the color-changing material composition are provided. Degradation of the color-changing membrane due to continuous lighting of a light source can be decreased, the increase in viscosity of the composition can be suppressed, and deterioration of rhodamine can be prevented by using the color-changing material composition and the color-changing membrane using the composition. |
1. A color-changing material composition which comprises a binder resin comprising a copolymer of a methacrylic ester and methacrylic acid represented by general formula (I) (Component A), at least one fluorescent coloring matter (Component B) and at least one of monomers and oligomers having a photopolymerizable ethylenically unsaturated group (Component C), general formula (I) being: wherein r represents (i) a substituted or unsubstituted linear, branched or cyclic alkyl group having 1 to 10 carbon atoms or (ii) —CH2—Ar, Ar representing a substituted or unsubstituted aromatic ring group having 6 to 20 carbon atoms, and m and n each represent an integer of 1 or greater. 2. A color-changing material composition according to claim 1, wherein R in general formula (I) represents methyl group, ethyl group, cyclohexyl group, cyclohexylmethyl group, hydroxyethyl group or benzyl group. 3. A color-changing material composition according to claim 1, wherein Component C is at least one of monomers and oligomers having a photopolymerizable ethylenically unsaturated group having hydroxyl group. 4. A color-changing material composition according to claim 1, which comprises 10 to 200 parts by weight of Component C based on 100 parts by weight of Component A. 5. A color-changing material composition according to claim 1, which comprises 0.1 to 15% by weight of a compound having epoxy group (Component D) based on an amount of an entire color-changing material composition. 6. A color-changing material composition according to claim 1, which comprises 0.1 to 10% by weight of Component B based on an amount of an entire color-changing material composition. 7. A color-changing material composition according to claim 1, wherein a weight-average molecular weight of Component A is in a range of 5,000 to 100,000. 8. A color-changing material composition according to claim 1, wherein a copolymer ratio q=m/(m+n) of Component A is in a range of 0.4 to 0.9. 9. A color-changing material composition according to claim 1, wherein the coloring matter of Component B comprises at least one fluorescent coloring matter selected from coumarine-based fluorescent coloring matters and at least one fluorescent coloring matter selected from rhodamine-based fluorescent coloring matters. 10. A color-changing membrane formed from a color-changing material composition described in claim 1. 11. A color-changing membrane according to claim 10, which is formed in accordance with photolithography. 12. A color-changing membrane according to claim 10, which changes a portion of incident light or entire incident light into light having a longer wavelength. 13. A color-changing membrane according to claim 12, wherein a light source of the incident light is an organic electroluminescence device or an LED device. |
<SOH> BACKGROUND ART <EOH>Since organic electroluminescence (“electroluminescence” will be referred to as “EL”, hereinafter) devices are completely solid devices, and displays having a light weight and a small thickness and driven under a small voltage can be prepared, various developments on the organic EL devices are being conducted. When the organic EL devices is used for displays, it is most urgently desired that a method for full color displaying is developed. For preparing a full color display, it is necessary that blue, green and red light emissions be finely arranged. At present, three method are available for this purpose, which are the method of arranging separate areas of the three colors, the method of using color filters and the method of color change. The method of color change has advantages in that a display having a great area is more easily provided in accordance with this method than in accordance with the method of arranging separate areas of the three colors and that the loss in the luminance is smaller in accordance with this method than in accordance with the method of using color filters. Therefore, the present inventors have been studying preparation of a full color display using an organic EL device in accordance with the method of color change. When a full color display is prepared in accordance with the method of color change, it is necessary that the color-changing membranes used for changing emitted blue light into green light and red light be finely patterned. The color-changing membrane is constituted with a fluorescent coloring matter and a resin in which the coloring matter is dispersed. For the fine patterning of the color-changing membrane, fine working on the resin itself is necessary. For this purpose, for example, a color-changing material composition using a basic resin such as a vinyl pyridine derivative or an aminostyrene derivative is used in Japanese Patent Application Laid-Open No. Heisei 9(1997)-208944; a color-changing material composition using a copolymer of an ethylenically unsaturated carboxylic acid is disclosed in Japanese Patent Application Laid-Open No. Heisei 9(1997)-106888; and a color-changing material composition which contains a compound having an unsaturated group obtained by the reaction of a reaction product of an epoxy compound and acrylic acid or methacrylic acid with a polybasic carboxylic acid or an anhydride thereof and at least one fluorescent compound selected from fluorescent coloring matters and fluorescent pigments, is disclosed in Japanese Patent Application Laid-Open No. Heisei 2000-119645. However, the above color-changing material compositions have drawbacks in that, when a color-changing membrane containing a rhodamine-based coloring matter is continuously irradiated with blue light emitted from an organic EL device, the intensity of light emitted from the rhodamine-based coloring matter decreases very quickly; that rhodamine is decomposed into a leuco compound, and the desired light emission cannot be obtained in the cases of some compositions; and that viscosity of the composition increases due to the reaction of rhodamine, and workability of the color-changing membrane is adversely affected in the cases of some compositions. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows a diagram exhibiting the construction of an organic EL device for full color displays used in the evaluation of durability in Examples and Comparative Examples. detailed-description description="Detailed Description" end="lead"? 1 means a glass substrate, 2 means a color-changing membrane, 3 means an anode, 4 means an organic EL light emitting layer, and 5 means a cathode. |
Chemotherapeutic agents |
The invention provides 1,2-substituted cyclic compounds useful for treatment of diseases or disorders arising from abnormal or inappropriate cell proliferation, such as tumour growth, tumour metastasis and associated angiogenesis, as well as pharmaceutical compositions comprising these compounds and their use in methods of treatment. |
1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: A and B are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; in which arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be connected with another ring through a single bond or fused with at least one other ring, and these rings optionally substituted at one or more positions with: alkyl, alkoxy, aryl, aryloxy, arylalkyl, arylalkyloxy, cyano, halogen, nitro, oxo, thiono, or CHnXm (where X is halogen, m is 1 to 3, and n is 3-m); S(O)R, or S(O)2R, (wherein R is selected from the group consisting of hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy); C(O)R, NHC(O)R, or (CH2)nC(O)OR, (wherein R is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy, and n is 0-11); S(O)2OR, OR, SR, B(OR)2, PR3, P(O)(OR)2, OP(O)(OR)2, or ═NOR, (wherein R is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl); or NRR′, NRS(O)2R′, SO2NRR′, or CONRR′, (wherein R is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl, and R′ is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy) and (i) where A is an alkyl, alkenyl or alkynyl group, B is an arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; (ii) where B is an alkyl, alkenyl or alkynyl group, A is an arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and wherein: the dotted line bonds of the central ring indicate the possibility of a double bond or a delocalised aromatic bond; C is CR1, nitrogen, oxygen, or sulfur; D is CR2, nitrogen, oxygen, or sulfur; E is CR3, nitrogen, oxygen, or sulfur; F is CR4, nitrogen, oxygen, sulfur, or nothing; provided that at least one of C, D, E, or F is CR; and R1, R2, R3, R4 are each independently selected from: hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, arylalkyl, arylalkyloxy, cycloalkyl, cyano, halogen, heteroaryl, nitro, or CHnXm (where X is halogen, m is 1 to 3, and n is 3-m); S(O)R, or S(O)2R, (wherein R is selected from the group consisting of hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy); C(O)R, NHC(O)R, or (CH2)nC(O)OR, (wherein R is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy, and n is 0-11); S(O)2OR, OR, SR, B(OR)2, PR3, P(O) (OR)2, OP(O) (OR)2, or —NOR, (wherein R is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl); NRR′, NRS(O)2R′, SO2NRR′, or CONRR′, (wherein R is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl, and R′ is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy); or one of R1 and R2, or R2 and R3, or R3 and R4 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle; and wherein: X and Y are linker groups each selected independently from the group consisting of: SO2NR, NRSO2, C(O)NR, NRC(O), C(S)NR, NRC(S), NRC(O)O, NRC(S)S, C(O)O, OC(O), S(O)2O, OSO2, SO2, OS(O), OSO2NR, NRS(O)2NR′, C(S)SSNR, NRSSC(S), P(O) (OR)NR′, NRP(O) (OR′), NRP(O)(OR′)O, CR═CR′, NRC(O)NR′, NR, C═NO—, —ON═C, C═N, N═C, N═N (→O)—, N (→O)=N, N═N, and a direct bond; where R and R1 are each selected independently from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, acyl, alkoxyacyl, aryloxyacyl, or aminoacyl; and (i) where X is NRSO2, Y is not NRC(O), NRC(S), NR, NRC(O)O or NRC(O)NR; (ii) where Y is NRSO2, X is not NRC(O), NRC(S), NR, NRC(O)O or NRC(O)NR; (iii) where X is a direct bond, Y not a direct bond; and (iv) where Y is a direct bond, X is not a direct bond. 2. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is CONR6, and R5 and R6 are each independently selected from the group consisting of H, alkyl, and aryl. 3. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is NR6CO, and R5 and R6 are as defined in claim 2. 4. A compound of Formula I as defined in claim 1, wherein X is NR5SO2, Y is CONR6, and R5 and R6 are as defined in claim 2. 5. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is SO2NR6, and R5 and R6 are as defined in claim 2. 6. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is NR6SO2, and R5 and R6 are as defined in claim 2. 7. A compound of Formula I as defined in claim 1, wherein X is CONR5, Y is CONR6, and R5 and R6 are as defined in claim 2. 8. A compound of Formula I as defined in claim 1, wherein X is CONR5, Y is NR6CO, and R5 and R6 are as defined in claim 2. 9. A compound of Formula I as defined in claim 1, wherein X is NR5SO2, Y is NR6SO2, and R5 and R6 are as defined in claim 2. 10. A compound of Formula I as defined in claim 1, wherein X is NR5CO, Y is NR6CO, and R5 and R6 are as defined in claim 2. 11. A compound of Formula I as defined in claim 1, wherein X is NR5CONR6, Y is NR7CONR8, R5 and R6 are as defined in claim 2, and wherein R7 and R8 are each independently selected from the group consisting of H, alkyl, and aryl. 12. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is NR6CS, and R5 and R6 are as defined in claim 2. 13. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is NR6CO2, and R5 and R6 are as defined in claim 2. 14. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is NR 6, and R5 and R6 as defined in claim 2. 15. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is NR6P(O)R7, R5 and R6 are as defined in claim 2, and wherein R7 is selected from the group consisting of H, alkyl, aryl, alkoxy, and aryloxy. 16. A compound of Formula I as defined in claim 1, wherein X is SO2NR5, Y is N═CH, and R5 is as defined in claim 2. 17. A compound of Formula I as defined in claim 1, wherein X is SO2O, Y is CONR5, and R5 is as defined in claim 2. 18. A compound of Formula I as defined in claim 1, wherein X is SO2O, Y is NR5CO, and R5 is as defined in claim 2. 19. A compound of Formula I as defined in claim 1, wherein X is OSO2, Y is CONR5, and R5 is as defined in claim 2. 20. A compound of Formula I as defined in claim 1, wherein X is SO2O, Y is SO2O. 21. A compound of Formula I as defined in claim 1, wherein X is SO2O, Y is OSO2. 22. The compound of Formula I as defined in claim 1, wherein A and B are each selected independently from the group consisting of pyrrolidine, piperidine, piperazine, morphonline, thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, furan, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, tetrazole, benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indene, naphthalene, indole, isoindole, indolizine, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine, pteridine, fluorene, carbazole, carboline, acridine, phenazine, and anthracene, optionally substituted at one or more positions with alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, oxo, ═S, S(O)R, SO2NRR′, S(O)2OR, SR, B(OR)2, PR3, P(O)(OR)2, OP(O)(OR)2, NO2, NRR′, N(O)R, OR, CN, C(O)R, NHC(O)R, (CH2)nCO2R, and CONRR′, wherein R and R′ are each independently selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyoxy; and n is 0-11. 23. The compound of Formula I as defined in claim 1, wherein the compound is selected from N-(2,6,-Diisopropylphenyl)-2-(2,6-diisopropylphenylsulfamoyl)-benzamide, N-phenyl-2-phenylsulfamoylbenzamide, N-[2-(4-methoxyphenylsulfamoyl)-phenyl]-isonicotinamide, N-[2-(4-methoxyphenylsulfamoyl)-phenyl]-4-nitro-benzamide, N-[2-(4-methoxyphenylsulfamoyl)-phenyl]-4-fluorobenzamide, N,N′-bis-(2,6-diisopropyl-phenyl)-phthalamide, 1-m-tolyl-3-[4-(3-m-tolyl-ureido)-pyridin-3-yl]-urea, 2-(4-methoxybenzenesulfonylamino)-N-pyridin-4-yl-benzamide, 2-(4-methoxy-benzamido)-N-pyridin-4-ylbenzamide, [2-(4-methoxyphenyl-sulfamoyl)-phenyl]-carbamic acid tert-butyl ester, benzene-1,2-disulfonic acid 1-[(4-methoxyphenyl)-amide] 2-pyridin-4-yl amide, benzene-1,2-disulfonic acid bis-[(4-methoxyphenyl)-amide], thiophene-2-sulfonic acid [2-(4-methoxyphenyl-sulfamoyl)-phenyl]-amide, 1,2-bis (2,4,6-triisopropyl-N-phenyl)-benzenesulfonamide, 2-[benzyl-(4-methoxyphenyl)-sulfamoyl]-N-pyridin-4-yl-benzamide, 2-(4-methoxyphenyl)-sulfamoyl]-N-pyridin-4-yl-benzamide, 4-fluoro-N-[2-(3,4,5-trimethoxybenzenesulfonylamino)-phenyl]-benzamide, 1H-pyrrole-2-carboxylic acid [2-(3,4,5-trimethoxybenzenesulfonyl-amino)-phenyl]-benzamide, and N-[2-(3,4,5-trimethoxybenzenesulfonylamino)-phenyl]-isonicotinamide. 24. A compound according to claim 2, wherein the compound is N-2,6,-diisopropylphenyl)-2-(2,6-diisopropylphenylsulfamoyl)-benzamide. 25. A compound according to claim 2, wherein the compound is 2-(4-methoxyphenyl)-sulfamoyl]-N-pyridin-4-yl-benzamide. 26. A compound according to claim 6, wherein the compound is thiophene-2-sulfonic acid [2-(4-methoxyphenylsulfamoyl)-phenyl]-amide. 27. A compound according to claim 3, wherein the compound is N-[2-(4-methoxyphenylsulfamoyl)-phenyl]-isonicotinamide. 28. A pharmaceutical composition comprising therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutical acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient. 29. A method for preventive and/or therapeutic treatment of a disease or disorder arising from abnormal or inappropriate cell proliferation, comprising administration to a subject in need thereof of a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof. 30. The method of claim 29, wherein said treatment is treatment of a neoplastic disease or neoplastic dependent disorder, including tumour growth, tumour metastasis and associated angiogenesis. 31. The method of claim 29 or claim 30, wherein said administration is in conjunction with another preventative or therapeutic treatment of a disease or disorder arising from abnormal or inappropriate cell proliferation, including angiogenesis. 32. The method of any one of claims 29 to 31, wherein said subject is a human. 33. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in the manufacture of a composition for preventative and/or therapeutic treatment of a disease or disorder arising from abnormal or inappropriate cell proliferation. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Neoplastic diseases are characterized by the uncontrolled proliferation of cells and are a major cause of death in mammals, including humans. Chemotherapeutic agents with various modes of action have been used to treat neoplastic disease, for example: antibiotics such as bleomycin and mitomycin; antimetabolites such as fluorouracil and methotrexate; microtubule polymerization inhibitors such as vincristine and colchicine; microtubule depolymerisation inhibitors such as paclitaxel and epothilone; and angiogenesis inhibitors such as angiostatin and neovastat. Specifically, there is a need for chemotherapeutic agents for treatment of neoplastic diseases that are safe for therapeutic use and that exhibit selective toxicity with respect to the pathological condition. Furthermore, there is a need for chemotherapeutic agents with modified or improved profiles of activity. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to a class of organic molecules that have antineoplastic activity. Such compounds are useful for the treatment of neoplastic diseases or neoplastic dependent disorders; illustrative of these are tumour growth, metastasis and associated angiogenesis. The present invention relates in particular to compounds that regulate and/or modulate abnormal or inappropriate cell proliferation, including any associated blood vessel growth (ie. angiogenesis). Accordingly, the present invention provides 1,2-substituted cyclic compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein: A and B are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; in which arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups may be connected with another ring through a single bond or fused with at least one other ring, and these rings optionally substituted at one or more positions with: alkyl, alkoxy, aryl, aryloxy, arylalkyl, arylalkyloxy, cyano, halogen, nitro, oxo, thiono, or CH n X m (where X is halogen, m is 1 to 3, and n is 3-m); S(O)R, or S(O) 2 R, (wherein R is selected from the group consisting of hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy); C(O)R, NHC(O)R, or (CH 2 ) n C(O)OR, (wherein R is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy, and n is 0-11); S(O) 2 OR, OR, SR, B(OR) 2 , PR 3 , P(O)(OR) 2 , OP(O)(OR) 2 , or ═NOR, (wherein R is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl); or NRR′, NRS(O) 2 R′, SO 2 NRR′, or CONRR′, (wherein R is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl, and R′ is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy). The following limitations apply to A and B in Formula I: (i) where A is alkyl, alkenyl, or alkynyl; B is an arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and (ii) where B is alkyl, alkenyl, or alkynyl; A is an arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group. In Formula I: the dotted line bonds of the central ring indicate the possibility of a double bond or a delocalised aromatic bond; C is CR 1 , nitrogen, oxygen, or sulfur; D is CR 2 , nitrogen, oxygen, or sulfur; E is CR 3 , nitrogen, oxygen, or sulfur; F is CR 4 , nitrogen, oxygen, sulfur, or nothing; provided that at least one of C, D, E, or F is CR; and R 1 , R 2 , R 3 , R 4 are each independently selected from: hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, arylalkyl, arylalkyloxy, cycloalkyl, cyano, halogen, heteroaryl, nitro, or CH n X m (where X is halogen, m is 1 to 3, and n is 3-m); S(O)R, or S(O) 2 R, (wherein R is selected from the group consisting of hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy); C(O)R, NHC(O)R, or (CH 2 ) n C(O)OR, (wherein R is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy, and n is 0-11); S(O) 2 OR, OR, SR, B(OR) 2 , PR 3 , P(O)(OR) 2 , OP(O)(OR) 2 , or ═NOR, (wherein R is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl); or NRR′, NRS(O) 2 R′, SO 2 NRR′, or CONRR′, (wherein R is selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl, and R′ is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, arylalkyl, and arylalkyloxy); or one of R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle. Also in Formula I: X and Y are linker groups each selected independently from the group consisting of: SO 2 NR, NRSO 2 , C(O)NR, NRC(O), C(S)NR, NRC(S), NRC(O)O, NRC(S)S, C(O)O, OC(O), S(O) 2 O, OSO 2 , SO 2 , OS(O), OSO 2 NR, NRS(O) 2 NR′, C(S)SSNR, NRSSC(S), P(O) (OR)NR′, NRP(O) (OR′), NRP(O)(OR′)O, CR═CR′, NRC(O)NR′, NR, C═NO—, —ON═C, C═N, N═C, N═N(→O)—, N(→O)═N, N═N, and a direct bond; where R and R′ are each selected independently from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, acyl, alkoxyacyl, aryloxyacyl, or aminoacyl (the above linker groups are shown with their left ends attached to the central ring and their right ends attached to the A or B ring). The following limitations apply to X and Y in Formula I: (i) where X is NRSO 2 , Y is not NRC(O), NRC(S), NR, NRC(O)O or NRC(O)NR; (ii) where Y is NRSO 2 , X is not NRC(O), NRC(S), NR, NRC(O)O or NRC(O)NR; (iii) where X is a direct bond, Y is not a direct bond; and (iv) where Y is a direct bond, X is not a direct bond. The present invention also provides pharmaceutical compositions useful for the treatment of neoplastic diseases or neoplastic dependent disorders that comprise a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The compositions of the present invention may be used for preventive or therapeutic treatment of diseases or disorders that involve uncontrolled proliferation of cells, such as tumour growth, tumour metastasis, and associated angiogenesis. Accordingly, the present invention also provides a method for preventive and/or therapeutic treatment of a disease or disorder involving abnormal or inappropriate cell proliferation, which comprises administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a human or other mammalian patient in need thereof. This treatment may be administered either alone or in conjunction with another preventative or therapeutic treatment of the disease or disorder. Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia. detailed-description description="Detailed Description" end="lead"? |
Data packet router for a mobile communication device |
A data packet router enables a mobile communication device to access a WAN such as the Internet via a PC connected to the WAN. The router comprises bearer plug-in modules which each enable connection between the mobile communication device and the computer over a different bearer. The PC is therefore used as an internet access point for mobile communication devices which can use any conventional bearer to connect to the PC (USB, RS232, Bluetooth wireless etc.). Hence, a mobile telephone could gain web access using conventional WAP or, with the present invention, it could also be connected to a PC using a convenient bearer and hence gain access to the internet via the PC. Because the router uses bearer plug-in modules, it is possible to write new bearer modules as and when new bearers are developed and to readily add them to upgrade existing implementations. This is valuable since new connectivity standards (and enhancements to old standards) are continually under development. |
1. A data packet router which can run on a computer connected to a WAN an which enables a mobile communication device to access the WAN via the computer, wherein the router comprises (a) bearer plug-in modules which each enable connection between the mobile communication device and the computer over a different bearer, and (b) a bearer discovery module that can dynamically and automatically recognise when an instance of the new bearer (relating to an installer bearer plug-in module) is attached to the computer when an end user upgrade the computer and can make that bearer available. 2. The router of claim 1 which uses PPP as a local link protocol to encapsulate data passing over the connection between the mobile communication device and the computer and hence allows the bearer to be treated as a serial data bearer. 3. The router of claim 1 in which the bearer plug-in modules each enable connection over one of the following bearers: direct cable via serial COM port; USB; IR; short range wireless. 4. The router of claim 1 comprising an extensible bearer abstraction layer capable of being augmented with new bearer abstraction code for new bearers. 5. The router of claim 1 which can run on a computer which is a PC. 6. The router of claim 1 in which the router further compromises a protocol plug-in which enables connection between the mobile communication device and the computer over a TCP/IP connection protocol. 7. The router of claim 1 in which the router enables the computer and the mobile communication device to share facilities and capabilities. 8. The router of claim 7 which enables one or more of the following actions: (a) browsing the internet from a browser running on the mobile computing device, with the internet connection routing through the computer, (b) synchronising contacts and diary entries between the mobile computing device and the computer; (c) backing up data on the mobile computing device onto an internet based back up server or onto the computer; (d) browsing data on the mobile computing device from the computer and directly using that data in an application on the computer; (e) writing a message on a messaging application on the computer and sending that message from the mobile computing device. 9. The router of claim 1 in which the router comprises protocol plug-ins which each enable connection between the mobile communication device and the computer over one of the following protocols: (i) EPOC PLP (ii) UDP/IP. 10. The router of claim 2 which enables the mobile communication device to access the WAN via the computer without requiring any software specific to the router to be loaded onto or be running on the mobile computing device because the mobile computing device needs only to use its existing serial data connection capabilities. 11. The router of claim 1 which can be run solely from a removable storage media connected to the computer without requiring any software installation on the mobile computing device or third party dependencies in order to execute. 12. The router of claim 6 in which the IP packets carry data and/or voice. 13. The router of claim 1 in which the router causes one or more serial ports on the computer to open as a modem and the router operates as a proxy for the mobile computing device connected to the computer. 14. The router of claim 1 in which the computer is also connected to a LAN and the router enables the mobile communication device to access the LAN via the computer. 15. The router of claim 1 capable of assigning temporary non-routable virtual IP address to several locally connected mobile communication devices. 16. The router of claim 15 able to intercept all incoming data packets for a given channel and then forward the data packets to the correct locally connected device associated with that channel. 17. The router of claim 1 further comprising a plug-in module for each different host/locally connectable mobile communication device. 18. A method of enabling a mobile computing device to access a WAN using a data packet router forming a part of a computer connected to the WAN, comprising the step of selecting a bearer plug-in module from a set of available bearer plug-in modules, each module enabling a connection between the mobile communication device and the computer over a desired bearer. 19. The method of claim 18 further comprising the step of the router using PPP as a local link protocol to encapsulate data passing over the connection between the mobile communication device and the computer to allow the bearer to be treated as a serial data bearer. 20. The method of claim 18 in which the bearer plug-in modules each enable connection over one of the following bearers: (i) direct cable via serial COM port; (ii) USB; (iii) IR; (iv) short range wireless. 21. The method of claim 18 comprising the step of augmenting an extensible bearer abstraction layer in the router with new bearer abstraction code for new bearers. 22. The method of claim 18 comprising the step of a bearer discovery module dynamically and automatically recognising when an instance of a new bearer (relating to an installed bearer plug-in module) is attached to a computer and making it available. 23. The method of claim 18 comprising the step of the router using a protocol plug-in which enables connection between the mobile communication device and the computer over a TCP/IP connection protocol. 24. The method of claim 18 comprising the step of the computer and the mobile communication device sharing facilities and capabilities. 25. The method of claim 24 comprising the step of one or more of the following actions being performed: (a) browsing the internet from a browser running on the mobile computing device, with the internet connection routing through the computer; (b) synchronising contacts and diary entries between the mobile computing device and the computer; (c) backing up data on the mobile computing device onto an internet based back up server or onto the computer; (d) browsing data on the mobile computing device from the computer and directly using that data in an application on the computer; (e) writing a message on a messaging application on the computer and sending that message from the mobile computing device. 26. The method of claim 18 comprising the step of the router selecting a further protocol plug-in from a set of protocol plug-ins which each enable connection between the mobile communication device and the computer over one of the following protocols: (i) EPOC PLP (ii) UDP/IP. 27. The method of claim 19 comprising the step of the mobile communication device accessing the WAN via the computer without using any software specific to the router running on the mobile computing device but instead using its existing serial data connection capabilities. 28. The method of claim 18 comprising the step of running the router solely from a removable storage media connected to the computer without requiring any software installation on the mobile computing device or third party dependencies in order to execute. 29. The method of claim 23 comprising the step of carrying data and/or voice in the IP packets. 30. The method of claim 18 comprising the step of the router opening one or more serial ports on the computer as a modem and the router then operating as a proxy for the mobile computing device connected to the computer. 31. The method of claim 18 comprising the step of the mobile computing device accessing a LAN via the computer. 32. The method of claim 18 comprising the step of the router assigning temporary non-routable virtual IP address to several locally connected mobile communication devices. 33. The method of claim 32 comprising the step of the router intercepting all incoming data packets for a given channel and then forwarding the data packets to the correct locally connected device associated with that channel. 34. The method of claim 18 comprising the step of the router selecting a plug-in module from a set of plug-in modules, each specific to a different host/locally connectable mobile communication device. 35. Computer software when stored on a carrier medium, the software enabling a data packet router to perform the method of claim 18 when running on the computer. 36. Computer software when transmitted over a network, the software enabling a data packet router to perform the method of claim 18 when running on the computer. 37. A computer comprising a router as defined in claim 1. |
<SOH> BACKGROUND TO THE INVENTION <EOH>1. Field of the Invention This invention relates to a data packet router for a mobile communication device. A data packet router is hardware or software which routes data packets (e.g. IP packets) to a device with a specific address. A mobile computing device includes without limitation handheld computers, laptop computers, mobile telephones, personal organisers and wireless information devices. 2. Description of the Prior Art Mobile communication devices typically connect to WANs (such as the internet) in one of two ways. First, some devices are able to connect to the internet over the PSTN using an internal modem. For example, a laptop computer may have an internal modem allowing it to access the internet over the PSTN. This approach to accessing the internet has several disadvantages—(i) it requires the user to locate a spare telephone socket for a telephone jack leading from the laptop and (ii) the internal modem adds cost. The second approach is to use any long-range wireless communication capabilities (e.g. GSM or UMTS etc.) that the device itself may posses to reach a gateway (e.g a WAP gateway) which is connected to the internet. However, using a wireless bearer such as GSM may be unreliable and slow. High bandwidth systems such as UMTS are likely to be costly. There has also been much speculation about allowing mobile communication devices to access a wired gateway or access point to the internet so that, when in range of such a gateway, they can take advantage of the lower data access costs, high bandwidth and reliability of wired networks. For example, it has been suggested that a GSM or UMTS mobile telephone might also be enabled with a short range wireless capability, such as Bluetooth™, so that when it came into range of an access point (a Bluetooth “pod”) connected by wire to the internet, it could preferentially connect to the internet via the Bluetooth pod as opposed to using a GSM WAP connection. When out of range, it would revert to the conventional GSM WAP approach. Similarly, it is also possible for 802.11 enabled mobile communication devices to dial into a 802.11 access point for a LAN; the access point is typically a stand alone unit comprising a radio transceiver; it may itself be directly wire connected to the internet, or may be connected to a PC which is wire connected to the internet. The 802.11 enabled mobile communication device can then access the internet via the access point. But this approach requires additional infrastructure investment in new hardware access points and hence fails to filly exploit, at low cost, the existing PC based infrastructure that exists in most organisations. Conventional PCs can connect to WANs such as the internet either by directly dialling out over a PSTN land line via an internal or external modem or connecting to a server over a LAN which in turn can either dial out over a PSTN land line using a modem or is permanently connected over a dedicated line. Many businesses have spent considerable sums in developing LANs and server gateways to the internet and these are now commonplace parts of a computer or communications infrastructure. Using this infrastructure to allow mobile communication devices to access the internet is a compelling concept. The prior art suggests that it is possible for a mobile communication device to access the internet via a PC itself connected to the internet (e.g. directly or via a server)—i.e. to use the ubiquitous PC itself as the access point. Reference may for example be made to WO 01/90853 and EP 1028560. However, these disclosures provide few details on how to actually implement such a system. It is also possible for remote PCs to dial into a server over a PSTN connection using Microsoft Remote Access Server (RAS). But this in essence amounts to allowing an external device to look into an organisation's computer infrastructure, as opposed to using that existing infrastructure to enable a wireless computing device to look outside to the internet via RAS. In theory, RAS can be used to allow a mobile computing device to access the internet via a PC running RAS, but it is difficult to configure and inflexible. |
<SOH> SUMMARY OF THE INVENTION <EOH>In a first aspect of the invention, there is a data packet router which can run on a computer connected to a WAN and which enables a mobile communication device to access the WAN via the computer, wherein the router comprises (a) bearer plug-in modules which each enable connection between the mobile communication device and the computer over a different bearer and (b) a bearer discovery module that can dramatically and automatically recognise when an instance of a new bearer (relating to an installed bearer plug-in module) is attached to the computer when an end-user upgrades the computer and can make that bearer available Hence, the present invention envisages, in one implementation, using a computer such as a PC as an internet access point for mobile communication devices. A mobile telephone could gain web access using conventional WAP or, with the present invention, it could also be connected to a PC and access the internet through the PC using the most convenient bearer available using an appropriate bearer plug-in module. The bearer plug-in modules may each enable connection over one of the following bearers: (i) direct cable via serial COM port; (ii) USB; (iii) IR; (iv) short range wireless. Plug-in modules for other kinds of bearer can also be deployed; the above list is non-exhaustive but represents the most common bearer types at this time. The router may comprise an extensible bearer abstraction layer capable of being augmented with new bearer abstraction code for new bearers. For example, a bearer abstraction layer may be included in each bearer plug-in module. These modules may therefore constitute an extensible bearer abstraction layer. Because the router uses bearer plug-in modules, it is possible to write new bearer modules as and when new bearers are developed and to readily add them to upgrade existing implementations. This is valuable since new connectivity standards (and enhancements to old standards) are continually under development. As an example, enhanced USB has recently been developed, as has Firewire. Bearer plug-ins for each of these can be written and deployed to upgrade existing implementations. An additional feature is that there is a bearer discovery module that can dynamically and automatically recognise when an instance of a new bearer (relating to an installed bearer plug-in module) is attached to a computer and can make it available. No user configuration is then needed at all, unlike conventional systems, such RAS. Bearer discovery module may be specific to a given bearer type. The router may use a serial data link protocol such PPP as a local link protocol to encapsulate data passing over the connection between the mobile communication device and the computer so that the bearer is treated as a serial data bearer. The router also comprises a dynamic protocol plug-in which enables connection between the mobile communication device an the computer over a TCP/IP connection protocol. Hence, data routed by the router may be IP packets carrying data and/or voice. Low cost VoIP is therefore possible with an implementation of the present invention—a mobile telephone could use relatively costly UMTS for voice when no PC with a router as described above was available, but could also connect to such a PC for lower cost VoIP. The router may further comprise protocol plug-ins which each enable connection between the mobile communication device and the computer over one of the following protocols: (i) EPOC PLP; (ii) UDP/IP. In one implementation, no software specific to the router needs to be loaded onto or be running on the mobile computing device. Hence, the router function can be run solely from a diskette, CD or other removable media running on the PC without requiring any software installation on the mobile computing device or third party dependencies in order to execute. Further, the PC itself does not need to know any information about the mobile communication device to enable access from the mobile communication device to the PC. The router can operate by causing one or more serial ports on the PC to open as a modem and the router operates as a proxy for the mobile computing device connected to the PC. The router can assign temporary non-routable virtual IP address to several locally connected mobile communication devices. The router is able to intercept all incoming data packets for a given channel and then forward the data packets to the correct locally connected device associated with that channel. The router may also comprise a plug-in module for each different host/locally connectable mobile communication device. The PC may also be connected to a LAN such that the router enables the mobile communication device to access the LAN via the PC. Some use cases for the present invention are: (a) browsing the internet from a browser running on the mobile computing device, with the internet connection routing through the computer; (b) synchronising contacts and diary entries between the mobile computing device and the computer; (c) backing up data on the mobile computing device onto an internet based back up server or onto the computer, (d) browsing data on the mobile computing device from the computer and directly using that data in an application on the computer, (e) writing a message on a messaging application on the computer and sending that message from the mobile computing device. The present invention therefore leverages the existing PC based internet communications infrastructure that already exists in most organisations, allows the mobile phone to view conventional web pages using a micro-browser (i.e. it is no longer limited to the relatively small number of WAP enabled sites, which in any event currently offer limited content) and means that wireless network charges are not incurred. For mobile professionals, being able to access the internet reliably and cheaply by using existing wire-based PC infrastructure is very useful—in many circumstances, one has easy access to someone else's PC, but one wishes to use ones' own wireless device to browse and perhaps store data. This is now possible with the present invention. Further, the present invention allows a combination of a user's mobile computing device and ordinary computer (e.g. desktop PC) to be operated as a single, seamless device, sharing facilities and capabilities. In a second aspect, there is a method of enabling a mobile computer device to access a WAN using a data packet router forming a part of a computer connected to the WAN, comprising the step of selecting a bearer plug-in module to enable connection between the mobile communication device and the computer over a desired bearer. In a third aspect, there is computer software when stored on a carrier medium, the software enabling a data packet router to perform the above method when tuning on the computer. In a fourth aspect, there is computer software when transmitted over a network, the software enabling a data packet router to perform the above method when running on the computer. In a final aspect, there is a computer comprising a router as defined in the first aspect. |
Process for preparing cross-linked polyolefins |
The present invention refers to a process for preparing cross-linked polyolefins, comprising the steps of adding a diazido compound of the formula (I) N═N═N—X—R—X—N═N=N wherein R represents an aryl, alkyl or aralkyl group having 3 to 20 carbon atoms and X stands for —CO—, —O—CO—SO2-, —PO2-, —PO3—, or -Si (═O)—, and a peroxide compound of the general formula (II) R1-X1-OO—X2—R2 wherein R1 and R2 are the same or different and represent hydrogen, an aryl, alkyl or aralkyl group having 3 to 20 carbon atoms and optionally comprising further peroxide groups, wherein one of R1 and R2 can form a ring, and X1 and X2 are the same or different and stand for a direct bond, —CO2— or —CO— to a polyolefin in powder or pellet form; mixing the product to obtain a mixture; extruding the mixture in an extruder at a temperature above the decomposition temperature of the diazido compound of formula (I) and of the peroxide compound of formula (II). |
1. A process for preparing cross-linked polyolefins having an improved melt strength and melt processability, comprising the steps of: (a) adding a diazido compound of the formula (I) N═N═N—X—R—X—N═N=N (I), wherein R represents an aryl, alkyl or aralkyl group having 4 to 20 carbon atoms and X stands for —CO—, —O—CO—, —SO2—, —PO2— or -Si (═O)—; and a peroxide compound of the general formula (II) R1-X1—OO—X2—R2 (II) wherein R1 and R2 are the same or different and represent hydrogen, an aryl, alkyl or aralkyl group having 3 to 20 carbon atoms and optionally comprising further peroxide groups, wherein one of R1 and R2 is not hydrogen and wherein R1 and R2 can form a ring, and X1 and X2 are the same or different and stand for a direct bond, —CO2—, or —CO—, to a polyolefin, wherein the ratio of the diazido compound to the peroxide compound is within the range of 1.0 to 4.0; (b) mixing the components of step (a) to obtain a mixture; (c) extruding the mixture obtained in step (b) in an extruder at a temperature above the decomposition temperature of the diazido compound of formula (I) and above the decomposition temperature of the peroxide compound of formula (II). 2. The process according to claim 1, wherein the mixture obtained in step (a) is extruded in the presence of a chemical and/or physical blowing agent. 3. The process according to claim 1, wherein the mixture obtained in step (a) is extruded in the presence of an aliphatic organic solvent selected from propane, n-butane, n-pentane, n-hexane, branched isomers or any mixtures thereof. 4. The process according to claim 1, wherein the diazido compound is of the formula (I) N═N═N—X—R—X—N═N=N (I), wherein R represents —(CH2)n—R1—(CH2)n— in which R1 represents an aryl or polyaryl, wherein the aryl can also be substituted by a branched or linear C1 to C6 alkyl, or (CH2)w group, w being 4 to 6, and in which n is 0, 1, or 2 and wherein X stands for —SO2—, —O—CO—, or —CO—. 5. The process according to claim 1, wherein, in formula (I), X stands for —SO2—. 6. The process according to claim 1, wherein the diazido compound is N3—SO2—R2-SO2—N3, wherein R2 represents an aryl group or an alkyl group having 4 to 8 carbon atoms. 7. The process according to claim 1, wherein the diazido compound is 1,6-di (sulfonazido)-hexane or 1,3-di (sulfonazido)-benzene. 8. The process according to claim 1, wherein the diazido compound is used in an amount of 5 to 25,000 ppm related to the amount of the polyolefin. 9. The process according to claim 1 any of the foregoing claims, wherein the peroxide compound is of the general formula (II) R1—X1—OO—X2—R2 (II) wherein R1 and R2 are the same or different and represent hydrogen, an aryl, alkyl or aralkyl group having 3 to 20 carbon atoms and optionally comprising further peroxide groups, wherein one of R1 and R2 is not hydrogen and wherein R1 and R2 can form a ring, and wherein X1 and X2 are the same or different and stand for a direct bond, —CO2— or —CO—. 10. The process according to claim 9, wherein the peroxide compound is 2, 5-dimethyl-2,5-di-(t-butylperoxy)-hexane. 11. The process according to claim 1, wherein the peroxide compound is used in an amount of 5 to 10,000 ppm related to the amount of the polyolefin. 12. The process according to claim 1, wherein the polyolefin is polypropylene, polyethylene, a copolymer or a mixture thereof. 13. An extrudate which is obtained by the process of claim 1. 14. Use of the extrudate of claim 13 for the preparation of a shaped or molded articles. 15. The use according to claim 14, wherein the shaped or molded articles is an articles for an automotive parts and/or packaging. 16. Use of a combination of a diazido compound of the formula (I) N═N═N—X—R—X—N═N=N (I), wherein R represents an aryl, alkyl or aralkyl group having 3 to 20 carbon atoms and X stands for —CO—, —SO2—PO2—, —PO3 or -Si (═O)—, and and a peroxide compound of the general formula (II) R1-X1-OO—X2—R2 (II) wherein R1 and R2 are the same or different and represent hydrogen, an aryl, alkyl or aralkyl group having 3 to 20 carbon atoms and optionally comprising further peroxide groups, wherein one of R1 and R2 is not hydrogen and wherein R1 and R2 can form a ring, and X1 and X2 are the same or different and stand for a direct bond, —CO2— or —CO—, for modifying the melt strength of polymers. 17. The use according to claim 16 for improving the melt processability of polymers. 18. The use according to claim 16 or claim 17 wherein the ratio of the diazido compound to the peroxide compound is within the range 1.0 to 4.0. 19. (canceled) 20. The process according to claim 2, wherein the mixture obtained in step (a) is extruded in the presence of an aliphatic organic solvent having 3 to 10 carbon atoms. 21. The process according to claim 20, wherein the aliphatic organic solvent has 3 to 8 carbon atoms. 22. The process according to claim 8, wherein the diazido compound is used in an amount of 10 to 10,000 ppm related to the amount of the polyolefin. 23. The process according to claim 22, wherein the diazido compound is used in an amount of 25 to 5,000 ppm related to the amount of the polyolefin. 24. The process according to claim 23, wherein the diazido compound is used in an amount of over 50 to 800 ppm related to the amount of the polyolefin. 25. The process according to claim 24, wherein the diazido compound is used in an amount of 100 to 400 ppm related to the amount of the polyolefin. 26. The process according to claim 11, wherein the peroxide compound is used in an amount of 25 to 5,000 ppm related to the amount of polyolefin. 27. The process according to claim 26, wherein the peroxide compound is used in an amount of 25 to 1,000 ppm related to the amount of polyolefin. 28. The use according to claim 16, wherein the polymer is a polyolefin. 29. The use according to claim 17, wherein the polymer is a polyolefin. 30. The use according to claim 28 or claim 29, wherein the polyolefin is selected from a polypropylene, polyethylene, a copolymer or a mixture thereof. |
Information processing device, information processing method, and information processing program |
The present invention is intended to provide a highly reliable and user-friendly information processing apparatus by mitigating the processing load of its CPU to increase the transfer rate at recording and enhance the usage efficiency of recording media. A host CPU 13 determines whether an information signal supplied from the apparatus under the control thereof is a moving picture signal from an instruction entered by user through a key operation block 14 or from the information included in the supplied information signal. If the supplied information signal is found to be moving picture information, the CPU 13 detects free blocks each made up of a plurality of clusters by referencing the FAT information of a hard disk 11 for example selected as a recording medium and records the moving picture information in unit of detected free blocks. If the supplied information signal is found not to be moving picture information, the CPU 13 records the detected signal to free clusters on a cluster basis. |
1. An information processing apparatus for recording an inputted information signal to a recording medium as one file, comprising: detection means for detecting a free area based on a block composed of a plurality of continuous clusters, which is a minimum recording unit on said recording medium; and recording control means for controlling, on the basis of a detection result obtained by said detection means, recording means to record said information signal to said block-basis free area on said recording medium. 2. The information processing apparatus according to claim 1, wherein said detection means detects said block-basis free area from said recording medium on which a recording area is regularly divided in unit of said block beforehand. 3. The information processing apparatus according to claim 1, further comprising: decision means for deciding whether said information signal is moving picture information; wherein, if said information signal is found by said decision means to be moving picture information, said recording control means controls said recording means to record said information signal to said block-basis free area on said recording medium. 4. The information processing apparatus according to claim 1, further comprising: file management means for forming, on said recording medium, a file management table containing information indicative of a link relationship of clusters in which information signals constituting a file are recorded and managing said file management table; wherein said detection means detects a free area by referencing said file management table. 5. The information processing apparatus according to claim 1, further comprising: file management means for forming, on said recording medium, a file management table containing information indicative of a link relationship of clusters in which information signals constituting a file are recorded and managing said file management table; and vacancy information table formation means for forming a vacancy information table composed of free cluster information onto a memory other than said recording medium by referencing said file management table; wherein said detection means detects a free area by referencing said vacancy information table. 6. The information processing apparatus according to claim 5, wherein said vacancy information table formation means forms said vacancy information table in a free time, which is arranged when said information signal is processed realtime. 7. The information processing apparatus according to claim 6, wherein said vacancy information table formation means forms said vacancy information table within a range of a processible data amount about said file management table set beforehand or to be set in accordance with said free time or within a processing time for forming said vacancy information table. 8. The information processing apparatus according to claim 5, further comprising: saving means for saving said vacancy information table formed in said memory to a nonvolatile recording medium. 9. The information processing apparatus according to claim 4, further comprising: a nonvolatile memory; start recording means for recording, to said nonvolatile memory, start information indicative to which file an information signal is to be recorded; invalidating means for invalidating, at the end of recording of an information signal, said start information recorded in said nonvolatile memory; halfway detection means for detecting on the basis of said start information whether there is any file halfway being recorded when a power-on sequence has started; and recovery means for recovering, if a file halfway being recorded is found, said file halfway being recorded by obtaining necessary information recorded in said nonvolatile memory by referencing said file management table of said file. 10. The information processing apparatus according to claim 4, further comprising: link information table formation means for forming a link information table containing information indicative of said cluster link relationship to continuous memory areas external to said recording medium by referencing said file management table; and read control means for controlling reading means for reading said information signals on the basis of information contained in said link information table. 11. An information processing apparatus for reading a file recorded to a recording medium, said recording medium is formed with a file management table containing information indicative of a link relationship of clusters in which information signals constituting said file are recorded, said information processing apparatus comprising: link information table formation means for forming link information table containing information indicative of said cluster link relationship to continuous memory areas external to said recording medium by referencing said file management table; and read control means for controlling reading means for reading said information signals on the basis of information contained said link information table. 12. The information processing apparatus according to claim 10 or 11, wherein said link information table formation means forms said link information table into a free time, which is arranged when said information signals are being processed realtime. 13. The information processing apparatus according to claim 12, wherein said link information table formation means forms said link information table within a range of a processible data amount about said file management table set beforehand or to be set in accordance with said free time or within a range of processing time for forming said link information table. 14. The information processing apparatus according to claim 10 or 11, wherein further comprising save means for saving said link information table formed on said memory areas into a nonvolatile recording medium. 15. An information processing method for recording an inputted information signal to a recording medium as one file, comprising the steps of: detecting a free area based on a block composed of a plurality of continuous clusters, which is a minimum recording unit on said recording medium; and controlling, on the basis of a detection result obtained by said detection means, recording means to record said information signal to said block-basis free area on said recording medium. 16. The information processing method according to claim 15, wherein said detection step detects said block-basis free area from said recording medium on which a recording area is regularly divided in unit of said block beforehand. 17. The information processing method according to claim 15, further comprising the step of: deciding whether said information signal is moving picture information; wherein, if said information signal is found in said decision step to be moving picture information, said recording control step controls said recording means to record said information signal to said block-basis free area on said recording medium. 18. The information processing method according to claim 15, wherein said recording medium is formed with a file management table containing information indicative of a link relationship of clusters in which information signals constituting a file are recorded and said detection step detects a free area by referencing said file management table. 19. The information processing method according to claim 15, wherein said recording medium is formed with a file management table containing information indicative of a link relationship of clusters in which information signals constituting a file are recorded; further comprising the step of: forming a vacancy information table containing cluster vacancy information, which is formed in a memory other than said recording medium, wherein said detection step detects a free area by referencing said vacancy information table. 20. The information processing method according to claim 19, wherein said vacancy information table formation step forms said vacancy information table in a free time, which is arranged when said information signal is processed realtime. 21. The information processing method according to claim 20, wherein said vacancy information table formation step forms said vacancy information table within a range of a processible data amount about said file management table set beforehand or to be set in accordance with said free time or within a processing time for forming said vacancy information table. 22. The information processing method according to claim 19, further comprising the step of: saving said vacancy information table formed in said memory to a nonvolatile recording medium. 23. The information processing method according to claim 22, further comprising the steps of: recording, to said nonvolatile memory, start information indicative to which file an information signal is to be recorded; invalidating, at the end of recording of an information signal, said start information recorded in said nonvolatile memory; detecting on the basis of said start information whether there is any file halfway being recorded when a power-on sequence has started; and recovering, if a file halfway being recorded is found, said file halfway being recorded by obtaining necessary information by referencing said file management table of said file. 24. The information processing method according to claim 22, further comprising the steps of: forming a link information table containing information indicative of said cluster link relationship to continuous memory areas external to said recording medium by referencing said file management table; and controlling reading means for reading said information signals on the basis of information contained in said link information table. 25. An information processing method for reading a file recorded to a recording medium formed with a file management table containing information indicative of a link relationship of clusters in which information signals constituting a file are recorded, said information processing method comprising the steps of: forming a link information table containing information indicative of said link relationship of clusters to continuous memory areas other than said recording medium by referencing said file management table; and controlling said reading means for reading said information signal on the basis of said link information table. 26. The information processing method according to claim 24 or 25, wherein said link information table formation step forms said link information table into a free time, which is arranged when said information signals are being processed realtime. 27. The information processing method according to claim 26, wherein said link information table formation step forms said link information table within a range of a processible data amount about said file management table set beforehand or to be set in accordance with said free time or within a range of processing time for forming said link information table. 28. The information processing method according to claim 24 or 25, comprising the step of: saving said link information table formed on said memory areas to a nonvolatile recording medium. 29. An information processing program for having a computer installed on an information processing apparatus for recording an inputted information signal to a recording medium on a file basis executes the steps of: detecting a free area based on a block composed of a plurality of continuous clusters, which is a minimum recording unit on said recording medium; and controlling, on the basis of a detection result obtained by said detection means, recording means to record said information signal to said block-basis free area on said recording medium. 30. The information processing program according to claim 29, wherein said detection step detects said block-basis free area from said recording medium on which a recording area is regularly divided in unit of said block beforehand. 31. The information processing program according to claim 29, further comprising the step of: deciding whether said information signal is moving picture information; wherein, if said information signal is found in said decision step to be moving picture information, said recording control step controls said recording means to record said information signal to said block-basis free area on said recording medium. 32. The information processing program according to claim 29, wherein said recording medium is formed with a file management table containing information indicative of a link relationship of clusters in which information signals constituting a file are recorded and said detection step detects a free area by referencing said file management table. 33. The information processing program according to claim 29, wherein said recording medium is formed with a file management table containing information indicative of a link relationship of clusters in which information signals constituting a file are recorded; further comprising the step of: forming a vacancy information table containing cluster vacancy information, which is formed in a memory other than said recording medium, wherein said detection step detects a free area by referencing said vacancy information table. 34. The information processing program according to claim 33, wherein said vacancy information table formation step forms said vacancy information table in a free time, which is arranged when said information signal is processed realtime. 35. The information processing program according to claim 34, wherein said vacancy information table formation step forms said vacancy information table within a range of a processible data amount about said file management table set beforehand or to be set in accordance with said free time or within a processing time for forming said vacancy information table. 36. The information processing program according to claim 33, further comprising the step of: saving said vacancy information table formed in said memory to a nonvolatile recording medium. 37. The information processing program according to claim 35 or 36, further comprising the steps of: recording, to said nonvolatile memory, start information indicative to which file an information signal is to be recorded; invalidating, at the end of recording of an information signal, said start information recorded in said nonvolatile memory; detecting on the basis of said start information whether there is any file halfway being recorded when a power-on sequence has started; and recovering, if a file halfway being recorded is found, said file halfway being recorded by obtaining necessary information by referencing said file management table of said file. 38. The information processing program according to claim 36, further comprising the steps of: forming a link information table containing information indicative of said cluster link relationship to continuous memory areas external to said recording medium by referencing said file management table; and controlling reading means for reading said information signals on the basis of said link information table. 39. An information processing program for having a computer installed on an information processing apparatus for reading a file recorded to a recording medium formed with a file management table containing information indicative of a link relationship of clusters in which information signals constituting a file are recorded execute the steps of: forming a link information table containing information indicative of said link relationship of clusters to continuous memory areas other than said recording medium by referencing said file management table; and controlling said reading means for reading said information signal on the basis of said link information table. 40. The information processing program according to claim 38 or 39, wherein said link information table formation step forms said link information table into a free time which is arranged when said information signals are being processed realtime. 41. The information processing program according to claim 40, wherein said link information table formation step forms said link information table within a range of a processible data amount about said file management table set beforehand or to be set in accordance with said free time or within a range of processing time for forming said link information table. 42. The information processing program according to claim 38 or 39, comprising the step of: saving said link information table formed on said memory areas to a nonvolatile recording medium. |
<SOH> BACKGROUND ART <EOH>Many information processing apparatuses (or recording/reproducing apparatuses) have been proposed and in wide use. The apparatuses are capable of recording moving pictures and still pictures to magnetic tapes as recording media and reproducing recorded moving pictures and still pictures. These information processing apparatuses include VTR (Video Tape Recorder), digital VTR, video camera, digital video camera, and so on. As the results of recent technological advances of random-accessible recording media such as hard disks and semiconductor memories in the reduction in size, the growth in recording density, and the enhancement in access speed, information processing apparatuses such as hard disk units and semiconductor memory recorders are proposed. The apparatuses use random-accessible recording media such as hard disks and semiconductor memories as removable mass storage media. Unlike tape recording media such as magnetic tapes, hard disks and semiconductor memories are random-accessible, so that, when moving pictures and still pictures are recorded on these random-accessible memories, the recorded pictures may be manipulated with ease, this advantage widening the ranges of their uses. A method is disclosed (for example, refer to Japanese Patent Laid-open No. Hei 08-221303) in which, when moving pictures and still pictures are recorded on disk medium as recording media, the recording areas and recording directions of moving pictures and still pictures are controlled in order to reproduce the recording moving pictures at high speeds. However, the information processing apparatuses using random-accessible recording media such as hard disks and semiconductor memories involve the following problems: (1) Transfer Rate When hard disks and semiconductor memories are used as recording media, it is necessary to correctly specify the addresses on a recording medium at the time of writing and reading information signals (or data) on the recording medium, which in turn requires some time for recording data to a desired area and reading data from a desired area, sometimes making the margin of the transfer rate not enough for the processing of moving picture information. For this reason, if, at the recording of moving picture information, the speed of recording the moving picture information to a recording medium is slower than that of supplying the moving picture information, a so-called overflow occurs, thereby sometimes having to forcibly end the recording processing because of the failure of the normal recording of the moving picture information. If, at the production of moving picture information, the reading of the moving picture information from a recording medium is not in for its reproduction, a so-called underflow occurs, thereby sometimes having to forcibly end the reproduction processing because of the failure of the normal reproduction of the moving picture information. (2) Usage Efficiency of Recording Media Although hard disks and semiconductor memories are huge in their storage capacities, they are not limitless, so that the storage capacity of each recording medium must be used without waste, thereby enhancing the usage efficiency as high as possible. (3) Load of Host CPU Even if moving picture information must be processed at high speeds for example, the processing by the host CPU (Central Processing Unit) of each information processing apparatus for controlling each component thereof must be executed relatively easily to mitigate its load to always ensure its stable operation in any processing, maintaining its reliability at high levels. (4) Compatibility with other Devices Exchanging information with an information processing apparatus, which uses a hard disk or a semiconductor memory as recording media, a personal computer for example, requires the use of a same file system for example, making it difficult to execute information exchange. (5) Installation of File Systems To solve the problem mentioned in (4) above, a simple method may be that a file system used on the information processing apparatus, which uses a hard disk and a semiconductor memory as recording media, is installed on an apparatus such as a personal computer for example with which data are to be exchanged. However, the installation of file systems requires time and labor, so that this approach must be avoided as long as possible. (6) Use of File Systems File systems are always required for recording data to hard disks and semiconductor memories. However, depending on the configurations of file systems, it may take some time to find out the address of a desired data recording area from the information of a file system, thereby resulting in a delay in a read/write operation. (7) Action against Power Failure If the power is shut off at the time of recording moving picture information due to power outage or other causes, the moving picture information already recorded may become unusable, for which some good measures must be taken. Thus, the use of random-accessible recording media such as hard disks and semiconductor memories involves the above-mentioned problems, which must be solved. Recently, the provision of various information processing apparatuses such as recording/reproducing apparatuses using hard disks and semiconductor memories as recording media is proposed, for which it is necessary to provide products cleared of all the above-mentioned problems, always operating with stability, high in reliability, and easy to use. It is therefore an object of the present invention to provide an information processing apparatus, which is cleared of the above-mentioned problems, high in reliability, and easy to use and an information processing method and an information processing program, which are for use on this information processing apparatus. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a block diagram illustrating a recording/reproducing apparatus (embodied as a digital video camera), which is an information processing apparatus to which one embodiment of the present invention is applied. FIG. 2A through FIG. 2C outline a FAT file system for use in the recording/reproducing apparatus shown in FIG. 1 . FIG. 3 shows available recording schemes “grid type”, “padded type”, and “general type”. FIG. 4 shows the characteristics of each of the recording schemes shown in FIG. 3 . FIG. 5 shows examples in which moving picture recording is executed by “grid type” recording used in the recording/reproducing apparatus shown in FIG. 1 and still picture and IT data recording is executed by “general type” recording. FIG. 6 is a flowchart indicative of the processing to be executed at the recording on the recording/reproducing apparatus shown in FIG. 1 . FIG. 7 is a flowchart indicative of the processing to be executed at the reproduction on the recording/reproducing apparatus shown in FIG. 1 . FIG. 8A and FIG. 8B show a relationship between the FAT information formed on the recording/reproducing apparatus shown in FIG. 1 and the data area clusters to which information signal is recorded. FIG. 9 shows an example in which FAT information is developed into the internal memory of a related-art recording/reproducing apparatus such as a personal computer. FIG. 10A through FIG. 10C show an example in which FAT information is developed into the internal memory of the recording/reproducing apparatus shown in FIG. 1 . FIG. 11 is a flowchart indicative of the processing to be executed in the reproduction mode in the recording/reproducing apparatus shown in FIG. 1 . FIG. 12 is a flowchart indicative of the processing for generating a cluster link table formed from FAT information in the recording/reproducing apparatus shown in FIG. 1 . FIG. 13 is a flowchart indicative of the reproduction, fast-forward, and fast-rewind operations to be executed in the reproduction mode in the recording/reproducing apparatus shown in FIG. 1 . FIG. 14A and FIG. 14B are a flowchart indicative of the reproduction, fast-forward, and fast-rewind operations to be executed in the reproduction mode in the recording/reproducing apparatus shown in FIG. 1 . FIG. 15A and FIG. 15B show the management of a cluster link table. FIG. 16 shows the generation of a free cluster map to be executed in the recording/reproducing apparatus shown in FIG. 1 . FIG. 17 is a flowchart indicative of the generation of a free cluster map to be executed in the recording/reproducing apparatus shown in FIG. 1 . FIG. 18A and FIG. 18B show the FAT information for use in the recording/reproducing apparatus shown in FIG. 1 . FIG. 19 shows the directory entry information for use in the recording/reproducing apparatus shown in FIG. 1 . FIG. 20 shows the update timings of the FAT information and directory entry information to be executed on the recording/reproducing apparatus shown in FIG. 1 . FIG. 21A and FIG. 21B show the recovery (or repair) of files made unusable due to the power failure at the recording on the recording/reproducing apparatus shown in FIG. 1 . FIG. 22A through FIG. 22E show the recovery (or repair) of files made unusable due to the power failure at the recording on the recording/reproducing apparatus shown in FIG. 1 . FIG. 23 is a flowchart indicative of the processing to be executed at the recovery (or repair) of files made unusable due to the power failure at the recording on the recording/reproducing apparatus shown in FIG. 1 . FIG. 24 shows another example of a measure, executable in the recording/reproducing apparatus shown in FIG. 1 , for preventing a file from being made unusable due to power failure at the recording in the recording/reproducing apparatus shown in FIG. 1 . FIG. 25A through FIG. 25F show still another example of a measure, executable in the recording/reproducing apparatus shown in FIG. 1 , for preventing a file from being made unusable due to power failure at the recording in the recording/reproducing apparatus shown in FIG. 1 . FIG. 26 shows the processing of forming a cluster link table to be executed at realtime processing. FIG. 27 shows the processing of forming a cluster link table to be executed at realtime processing. FIG. 28A and FIG. 28B show free times to be provided at the times of recording and reproduction, which are realtime processing, of information signals. FIG. 29 is a flowchart indicative of the processing of forming a cluster link table to be executed at the time of recording. FIG. 30 is a flowchart indicative of another example of the processing of forming a cluster link table to be executed at the time of recording. FIG. 31 is a flowchart indicative of the processing of forming a cluster link table to be executed at the time of reproduction. FIG. 32 is a flowchart indicative of another example of the processing of forming a cluster link table to be executed at the time of reproduction. FIG. 33 shows an example of a free cluster map to be formed from FAT information. detailed-description description="Detailed Description" end="lead"? |
Method and apparatus for a medical image processing system |
Disclosed is a medical image processing system comprising a medical image storage server for storing digital image data provided by means such as computerized tomography or magnetic resonance image apparatus in a medical image database; and an image processing system which is coupled to said medical image storage server and to several client computers by TCP/IP protocol; wherein said image processing system comprises a user interface unit which converts the user's command into an electric signal and outputs said electric signal; an image processor unit which reads a medical image out of said medical image database, performs an image processing program comprising a medical image controlling algorithm and outputs a result signal; and an output interface unit which receives said result signal and converts said result signal into a format which can be recognized by a user. |
1. A medical image processing system comprising: a medical image storage server for storing digital image data provided by means such as computerized tomography or magnetic resonance image apparatus in a medical image database; and an image processing system which is coupled to said medical image storage server and to several client computers by TCP/IP protocol; wherein said image processing system comprises a user interface unit which converts the user's cammand into an electric signal and outputs said electric signal; an image processor unit which reads a medical image out of said medical image database, performs an image processing program comprising a medical image controlling algorithm and outputs a result signal; and an output interface unit which receives said result signal and converts said result signal into a format which user can recognize. 2. The medical image processing system of claim 1, wherein said image processing program embedded in said image processor unit comprises both an ordinary digital image processing algorithm and an organ-searching algorithm. 3. The medical image processing system of claim 1, wherein said image processing system transfers said result image to each client computer and relays information among said client computers. 4. A medical image processing method comprising the steps of: providing a menu screen as a window frame on a display means; converting a command of a user, which is received through an input interface unit, into a control signal and transferring said control signal to an image processor unit; analyzing said control signal; loading an image corresponding to said control signal and displaying said image on the displaying means; receiving an image processing control signal from the user; reading an image processing algorithm embedded in said image processor and performing said algorithm; displaying a result image acquired by performing said algorithm on a displaying means; and storing “result data”, which is obtained according to the command of the user, in a specific database. 5. The medical image processing method of claim 4, wherein said result image displayed on said displaying means comprises organ images, each of which has a unique color and a plurality of pixels, and a palette according to a ratio of the volume of the organ. 6. The medical image processing method of claim 4, wherein said image processing algorithm comprises both an ordinary digital image processing algorithm and an organ-searching algorithm. 7. The medical image processing method of claim 6, wherein said ordinary digital image processing algorithm comprises an image-leveling algorithm and an image-coloring algorithm. 8. The medical image processing method of claim 6, wherein said organ-searching algorithm for extracting an image of a liver comprising: (A) a contrast ratio calculating step which further comprises: (a-1) a pre-processing step in which background and muscles of the image is removed to leave organ images only; (a-2) a sample extracting step in which the range of brightness values of said organ images is estimated and sample data concerning a ratio of each brightness value of a liver are extracted; and (a-3) a position searching step in which the position of a body in each slice is determined and an approximate position of a liver and a spleen of the body is determined thereby acquiring their coordinate value; (B) a template generating step which further comprises: (b-1) a step in which a leveled image of an organ is generated and a mean value is calculated by closing a binary image and performing a subtraction between said binary image and said leveled image; (b-2) a step in which a template image is selected by comparing a ratio of a brightness value in a mesh of an input image to a ratio of a brightness value of said extracted sample, a subtraction is performed between said leveled image and each of a number of difference images, which are generated according to a difference between said ratio of the brightness value in the mesh of the input image and said ratio of the brightness value of the extracted sample, and a template image is extracted using a mean-value comparison; and (b-3) a step in which an image describing the outline of an organ is extracted by opening and enlarging said selected template image; and (C) an image adjusting step which further comprises: (c-1) a step in which a subtraction is performed on a binary image in order to generate a natural outline without losing information of an original image; and (c-2) a step in which the gaps among pixels are recognized and the inside of the organ is filled in without modifying said outline of the organ. 9. The medical image processing method of claim 6, wherein an algorithm for extracting a lung cancer image comprises: (A) a lung segmentation step which further comprises: (a-1) a histogram sliding step in which the gray values of all pixels in an original image are slid by a predetermined offset in order to make the original image brighter; (a-2) a thorax segmentation step in which the pixels of the slid image, which are darker than a predetermined gray value, are eliminated; (a-3) an equalization step in which said thorax segmented image is converted into a histogram-converted image in order to be distributed in all scales; (a-4) an image conversion step in which said thorax segmented image is divided into two parts according to a histogram containing frequencies of values of gray levels wherein the mean value becomes a boundary line; (a-5) a boundary extracting step in which only a boundary line of said converted image is extracted in order to eliminate a bronchus image from the lung area; (a-6) a boundary tracing step in which right and left lungs are eliminated from the bronchus area along said extracted boundary line; (a-7) an image synthesizing step in which the original image and the image of said traced boundary line is synthesized; (a-8) an adjusting step in which the thickness of said boundary line is adjusted in order to reduce a difference, which occurs when an inside and an outside of each of right and left lung are recognized; and (a-9) a boundary filling step in which an inside and an outside of each of right and left lungs are recognized by assigning predetermined gray values to the pixels, which is inside said boundary line; (B) a step in which said boundary image is enlarged using a morphological filter in order that the lung image contains lung cancer tissue; (C) a step in which the pixels having gray values larger than a predetermined value in said lung segmented image are eliminated and the clusters larger than a predetermined number of pixels are selected to be suspected lung cancer tissues; (D) a step in which a standard deviation of each pixel is calculated using a histogram of said cluster, which is suspected lung cancer tissue; and (E) a lung cancer extracting step in which a lung cancer tissue is distinguished from the partial volume. 10. The medical image processing method of claim 6, wherein the organ-searching algorithm for extracting a kidney image from a computerized tomography image of an abdomen, which is photographed without using a contrast agent, comprising: (A) a single slice processing step which further comprise: (a-1) a step in which an area, which has a contrast value of a predetermined range near a peak value among brightness values of spines in a single slice, is defined as a kidney; (a-2) a step in which a binary image is generated by converting the pixels of the images in reference to the threshold value; (a-3) a step in which a plurality of pixels and holes are recognized and the ratio of holes to the whole area of kidney is calculated; (a-4) a step in which a mesh image is generated by analyzing a relation between the number of holes and said ratio; (a-5) a step in which the lung area from said kidney image is extracted in reference to the coordinate values of pixels forming the kidney image, by searching the pixels connected one another lattice-wise; (a-6) a step in which a template is generated by enlarging a mesh image of said kidney image, from which lung area is eliminated, and opening the neighboring pixels; (a-7) a step in which a subtraction is performed between said template image and said binary image in order to extract from said binary image an area, which corresponds to said template image area,; and (a-8) a step in which the gaps between pixels of holes inside said subtracted kidney image are recognized and filled in; and (B) a whole slices processing step which further comprises: (b-1) a step in which an overlapped image is generated by adding all the pixel values in each slice processed by said single slice process and a mean value is calculated; (b-2) a noise reduction step in which the pixels outside said template image is removed by subtracting template image area excessively enlarged to be larger than said overlapped image; and (b-3) an object extraction step in which an object consisting of the largest number of pixels of objects is recognized and extracted. 11. The medical image processing method of claim 6, wherein the organ-searching algorithm for calculating a volume of a stomach comprising: (A) a pre-processing step in which a background of an abdomen image is eliminated and said abdomen image is leveled in order to maximize a difference between brightness values in an organ image; (B) a searching step in which a stomach image, which is divided into a part filled with foodstuffs and the other part filled with air, is extracted by generating histograms of both images, analyzing brightness values and position information; (C) an adding step in which the stomach areas which are respectively extracted from each histogram are merged; and (D) a volume calculating step in which the volume of the stomach is calculated using the information stored in an image header of said extracted stomach. 12. The medical image processing method of claim 6, wherein the organ-searching algorithm for extracting a liver image from a computerized tomography image of an abdomen, which is photographed using a contrast agent, comprising: (A) a step in which a seed image made up of pixels which forms a liver image is generated; (B) a step in which a mesh image of an organ is generated by comparing the distribution of brightness values of an input image in reference to the portion value of said seed image, (C) an area separating step in which a noise area is separated by recognizing a pixel in the lung image and searching for all pixels connected to that pixel; (D) a first extraction step in which an area having a brightness value, which varies from a value of vessel comprising kidney to a mean value of the mesh image, is included in the area of the liver; (E) a second extraction step in which all the holes in the image of the first extraction step are filled; (F) a step in which a template, which is used as a frame for subtracting an organ, which is to be extracted from a binary image, is generated; (G) a step in which the gaps between pixels are recognized and small holes inside the organ image are filled; and (H) a step in which the kidney image is extracted from the image containing a kidney image. 13. The medical image processing method of claim 6, wherein said organ-searching algorithm is used to calculate a volume and a ratio of panniculum according in reference to the pixel values of panniculum in a computerized tomography image. 14. The medical image processing method of claim 6, wherein said organ-searching algorithm is used to calculate volumes and ratios of skeletal muscles and smooth muscles in reference to the pixel values of muscles in a computerized tomography image. 15. The medical image processing method of claim 6, wherein said organ-searching algorithm is used to calculate volumes and ratios of hard bones and cartilages in reference to the pixel values of bones in a computerized tomography image. 16. The medical image processing method of claim 7 to claim 15, wherein the volume calculation of said organ-searching algorithm is calculated by a formula which is [area of one pixel×(((number of pixels having the first CT value of CT values of an organ in first slice)×(corresponding ratio)+ . . . +number of pixels having the last CT value of CT values of an organ in first slice×corresponding ratio) +(number of pixels having the first CT value of CT values of an organ in last slice×corresponding ratio+ . . . +number of pixels having the last CT value of CT values of an organ in last slice×corresponding ratio)×{fraction (1/2)}+(number of pixels having the first CT value of CT values of an organ in the second slice to the second to last slice×corresponding ratio+ . . . +number of pixels having the last CT value×corresponding ratio)×a distance between slices). |
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