A method for acquiring seismic data comprises operating a seismic vessel towing at least one of a seismic streamer with a plurality of seismic sensors and a seismic source. The inline distance between the vessel and one or more other vessels is adjusted according to a predefined function, where the seismic vessels travel along offset seismic acquisition lines, by increasing and reducing the in-line distance during the acquisition of the seismic data.

The present invention generally relates to marine seismic prospecting, and in particular to seismic prospecting methods using multiple vessels.
Petrochemical products such as oil and gas are ubiquitous in society and can be found in everything from gasoline to children's toys. Because of this, the demand for oil and gas remains high. In order to meet this high demand, it is important to locate oil and gas reserves in the Earth. Scientists and engineers conduct "surveys" utilizing, among other things, seismic and other wave exploration techniques to find oil and gas reservoirs within the Earth. These seismic exploration techniques often include controlling the emission of seismic energy into the Earth with a seismic source of energy (e.g., dynamite, air guns, vibrators, etc.), and monitoring the Earth's response to the seismic source with one or more receivers in order to create an image of the subsurface of the Earth.
Each receiver may include, for example, a pressure sensor and/or a particle motion sensor in proximity to one another. The pressure sensor may be, for example, a hydrophone that records scalar pressure measurements of a seismic wavefield. The particle motion sensor may be, for example, a three-component geophone that records vectorial velocity measurements of the seismic wavefield. By observing the reflected seismic wavefield detected by the receiver(s) during the survey, the geophysical data pertaining to reflected signals may be acquired and these signals may be used to form an image indicating the composition of the Earth near the survey location.
Marine seismic surveys generally involve towing one or more streamer cables comprising a plurality of receivers with a seismic vessel. The number of receivers placed in the streamer and the relative distance between the receivers generally determines the quality of seismic data that is recorded. Improving seismic data collection has traditionally involved increasing the length of streamer cables and the density of receivers included therein. However, the longer the streamer cables, the more difficult it becomes to keep streamer cables separated and in a desired configuration, for example, when turning the seismic vessel or maneuvering the seismic vessel in icy or obstructed waters.

Seismic data acquisition with varying distance between seismic vessels


Dietary fiber are derived from the tapioca pulp fiber that is a by-product of tapioca starch milling operations. The tapioca fiber may be refined through an enzymatic destarching step to provide a fiber comprising at least 70% total dietary fiber, of which at least 12% is soluble dietary fiber. The fiber may be further refined by bleaching. Acceptable foods may be prepared comprising unrefined or refined tapioca fiber.

High fiber diets have been promoted over the past several years because of the potential health benefits they offer. High fiber diets are reported to reduce the risk of colon and rectal cancers and to reduce blood serum cholesterol levels. Because dietary fiber is not well digested by humans, dietary fiber ingredients are non-caloric and contribute to a reduction in total food calories to the extent that they are used as a replacement for caloric ingredients such as carbohydrates, proteins, and fats.
The total dietary fiber (TDF) of a food or a food ingredient comprises two components: soluble dietary fiber (SDF) and insoluble dietary fiber (IDF). It is reported that the soluble dietary fiber component is the critical component in reducing serum cholesterol. It is reported that insoluble dietary fiber health benefits achieved by consuming the fiber.
A number of dietary fibers are presently marketed as ingredients for use in formulating "healthy" food products. These fiber-containing, nutritionally-fortified, food ingredients are characterized by different fiber contents, with the highest percentage of SDF (70%) reported for Psyllium and the highest TDF (99%) reported for alpha-cellulose. The dietary fiber contents of other fiber sources are: beet fiber (75% TDF; 24% SDF); corn bran (90% TDF; 2% SDF); oat bran (20-25% TDF; 12% SDF); refined oat bran (97% TDF; 1% SDF); rice bran (27-35% TDF; 2-6% SDF); wheat bran (40% TDF; 0% SDF); pea fiber (45% TDF; 5% SDF); potato fiber (75% TDF; 15-20% SDF); Psyllium husk (87% TDF; 70% SDF); and soy fiber (75% TDF; 15% SDF).
It has been discovered that tapioca fiber, which is a by-product of the tapioca starch milling process, may be refined by the removal of residual starch to yield a refined fiber containing approximately 70% TDF and 12% SDF. The crude tapioca fiber or pulp which is the direct by-product of starch milling contains approximately 67% starch, 30% TDF and 5% SDF, on a dry-weight basis. The tapioca root in various forms (e.g., cassava or manioc; poi (Hawaii); and farina (South America and the West Indies) has been used as a source of starch in the human diet.
It has been discovered that by destarching the unrefined tapioca fiber by-product, a bland, functionally compatible dietary fiber high in TDF and SDF may be obtained. Most fiber refining processes yield high TDF and IDF levels but reduce SDF levels. Thus, it is unexpected that a product containing high amounts of both fibers may be achieved by refining a raw fiber source.
As a further advantage, it has been discovered that the unrefined tapioca fiber (as well as the refined fiber) may be used in certain human foods (e.g., cereals) wherein its unique starch and fiber components provide functional benefits to the foods.
Many foods in the bread and cereal product group are nutritionally fortified by the addition of various fibers. Serious functional problems are frequently encountered in formulating foods containing high fiber ingredients. These problems include off-flavors and colors contributed by the fiber ingredient, together with textural problems such as lack of volume or expansion in baked goods or cereals, non-uniform texture, unpredictable water holding and/or absorption characteristics, interference with the production of extruded and expanded cereals or snacks, and other related problems.
One solution to these problems has been to refine the fiber so as to eliminate the color, flavor and non-uniform texture problems. However, the refinement process usually eliminates the SDF component of the fiber.
Other means that have been suggested for formulating foods with high fiber content include preparing a fiber ingredient to contain a specific particle size to provide a food having a density within a specified range. For example, U.S. Pat. No. 4,759,942, issued Jul. 26. 1988, to Von Fulger, discloses a process for producing a high fiber breakfast cereal, wherein the fiber is used at 3-9% of the cereal and the fiber is a bran (obtained from the outer layer of grains) material having an average particle size from 5-100 microns which produces an extruded cereal having a specific density of from 0.15 to 0.40 g/cc.
It is now been found that by employing an enzymatic process to refine tapioca fiber, the SDF content of the fiber is maintained and the components of the unrefined tapioca fiber which add caloric value or detract from its use in
food formulation are effectively removed. The enzymatic destarching process may be combined with a bleaching process which also preserves the SDF content of the fiber while improving its functional characteristics, and it may be combined with particle size control to improve texture and color. Thus, a food ingredient is provided which may be used to nutritionally fortify a variety of food products by providing high TDF and SDF contents.
It has also been found that in contrast to bran derived from grains. unrefined tapioca pulp fiber may be used to fortify cereals without having an unacceptable impact on cereal functionality or quality.

Dietary fiber derived from tapioca and process therefor

National Starch and Chemical Investment Holding Corporation


A shaped screen rotates through one or more projected images of two or more projectors operating simultaneously, resulting in a dynamic, kinetic image surface which may be viewed equally well from a plurality of angles, up to 360° horizontally. By utilizing at least two projectors, the resultant composite image on the rotating screen is not only optimally viewed from any angle, but it is also animated by the movement of the screen itself, as well as by any animation within the projected image.

Most image projection systems consist of a projector and a flat screen. The projector produces an image through still slides, moving film or video. The flat screen receives the projected light and provides viewers with a planar image that is viewable from either one or both sides of the screen. One drawback associated with conventional projection systems that project onto a flat screen is that the picture is best viewed when the viewer's line of sight is precisely normal to the plane of the picture. In such systems, special consideration must be given to the positioning of the display within its environment because, typically, conventional projection systems, such as those used in movie theaters, cannot be viewed from the rear or extreme sides. Thus, the area within which a viewing audience can be accommodated is limited to locations with suitable sight lines. This ideal condition is difficult to realize when several people wish to view the picture simultaneously from varied locations.
Sometimes multiple flat screens are used in conjunction with each other to partially surround an audience with imagery, or to place imagery in the center of a theatre which can be viewed from multiple sides. What all these systems have in common is that the screen itself provides a static framework onto which a still or moving image is projected. Any movement or dynamism is provided exclusively by the medium which is projected; the environment for the projected light is always static, and the view of any one screen is optimal for only a relatively narrow angular displacement from the center of that screen.
In an attempt to overcome the viewing limitations associated with conventional projection systems, the present invention can provide up to a 360° viewing system including a shaped, revolving screen. Projecting an image on a shaped, revolving screen presents several problems that will be apparent to those of skill in the art. First, the shape of the image surface (the screen) is not flat, but rather is contoured. Second, the screen is not static, it is dynamic in its rotation around a center axis. The varying shape of the screen, the screen's movement, its resultant cone of projection, and the screen's angular displacement from the projection device create a constantly changing area of projection. The problem is twofold. First, glare from the projection source is apparent to a viewer standing on the opposite side of the rotating screen around one or more of its edges as it moves. Second, the resultant spill-light of portions of the image that miss the screen as it rotates fall upon the background surface of the theatre, its ceiling or floor surfaces, creating distracting patterns of light.
Additionally, when the projection axis of the system is not perpendicular to the viewing screen, a portion of the projected image may appear distorted (e.g., stretched or compressed). This distortion is commonly known as keystone distortion. For example, if the projector is situated above a line normal to the viewing area of the screen, then the image must be projected downward to the screen. As a result, the upper portion of the image may appear expanded or stretched in relation to the lower potion of the image, or the lower portion may appear condensed or contracted compared to the upper portion. The projected image may thus take on a trapezoidal or keystone shape. Depending upon the resolution or detail of the image being projected, the distortion may significantly degrade one's appreciation of the image. The present invention addresses these and other needs.

System and method for projecting images onto a moving screen


One cycle is corrected every charging/discharging cycle in accordance with a cycle deterioration accelerating coefficient. The corrected one cycles are accumulated. A storage period is corrected in accordance with a storage deterioration accelerating coefficient every hour. The corrected storage periods are accumulated. In the storage period, a rechargeable battery is stored with the terminal voltage higher than a predetermined voltage. A deterioration coefficient is obtained as the product of a cycle deterioration coefficient calculated in accordance with the accumulated cycle number, and a storage deterioration coefficient calculated in accordance with the accumulated value of the storage periods (Step S42). If the deterioration coefficients falls within the range 0.3 to 0.7 (Step S43, 44: NO), the setting voltage in constant-voltage and constant-current charging operation is decreased from 4.2 to 4.1 V (S45). If it is smaller than 0.3 (S43: NO, S44: YES), the setting voltage is decreased to 3.8 V (S46).

1. Field of the Invention
The present invention relates to a method for charging a rechargeable battery at a constant voltage and a constant current, and a battery pack that charges a rechargeable battery based on this method.
2. Description of the Related Art
In the case where rechargeable batteries, typically, lithium ion batteries are charged, the batteries are charged at a constant current with the maximum of terminal voltage being limited to a setting voltage (constant current charging stage), while after the terminal voltage reaches the setting voltage the batteries are charged at a constant voltage (constant voltage charging stage). This charging method is referred to as constant-current and constant-voltage charging method, and is often used for rechargeable batteries. In some of this type of charging methods, before the charging operation is switched from the constant current charging stage to the constant voltage charging stage, the charging voltage or the charging current is gradually reduced. On the other hand, rechargeable batteries will be gradually deteriorated with the number of repeated charging/discharging cycles or if the rechargeable batteries are left standing (stored) for a long time after charged. If the deterioration degree of a rechargeable battery gets larger, the fully-charged capacity (FCC: Full Charge Capacity) or the safety may decrease. For this reason, it is important to grasp the degree of deterioration of rechargeable battery and to suppress the deterioration degree.
The life of a rechargeable battery can be determined by the degree of deterioration of rechargeable battery. The actual capacity (capacity equivalent to FCC) of a rechargeable battery is a capacity which can be substantially discharged from the rechargeable battery. The life and the actual capacity of a rechargeable battery will decrease with the number of repeated charging/discharging cycles or if the rechargeable battery is left standing for a long time. However, there is a tendency that the life and the actual capacity of a rechargeable battery will also decrease with the value(s) of setting voltage and/or setting current in charging operation. To address this, Japanese Patent Laid-Open Publication No. JP 2008-5644 A discloses a method that, in order to reduce (decrease) of actual capacity and increase the life of a rechargeable battery, decreases the setting voltage with the number of repeated charging/discharging cycles of the rechargeable battery.
Also, JP 2008-228492 A discloses a method which detects any of the internal resistance, actual capacity (learning capacity) and the number of charging/discharging cycles of a rechargeable battery to determine the deterioration state (degree of deterioration) of the rechargeable battery, and decreases the setting voltage depending on the determined deterioration state. In addition, JP 2002-236154 A discloses a method that corrects the decrease of the setting voltage by reducing the leaning capacity in accordance with the counted number of charging cycles and the elapsed storage time of the battery.
However, in the method disclosed in JP 2008-5644 A, since the setting voltage is decreased simply depending on the counted number of the charging/discharging cycles or the accumulated value of the charged/discharged capacities (capacities which are charged and/or discharged), even if the life of the rechargeable battery can be longer, the setting voltage is decreased without evaluation of the actual degree of deterioration. Also, in the method disclosed in JP 2008-228492, although a table or function is predetermined by modeling relationship between the deterioration state and the indices (e.g., internal resistance, actual capacity, and the number of charging/discharging cycles of the rechargeable battery) so that the deterioration state is determined based on the table or function, the decrease of setting voltage is not taken into consideration when the deterioration state is determined. Also, in the method disclosed in JP 2002-236154, this method is aimed at accurately correcting the learning capacity but is not directed to suppress the deterioration degree of the rechargeable battery.

Rechargeable battery charging method and battery pack capable of suppressing deterioration degree


A method for manufacturing a lithium secondary battery includes a first step of dispersing a conductive material in a solvent to prepare a conductive slurry; and a second step of mixing the prepared conductive slurry, a positive electrode active material and a binder to prepare a positive electrode mixture layer-forming slurry; wherein the first step is conducted so that a ratio of a particle size at 10% accumulation to a particle size at 90% accumulation, which are based on a particle size distribution measurement of the conductive material, is 10 or more and 200 or less.

1. Field of the Invention
The present invention relates to a method for manufacturing a lithium secondary battery (typically a lithium ion battery). In more detail, the present invention relates to a method for manufacturing a positive electrode of the battery.
2. Description of Related Art
A lithium secondary battery including a lithium ion battery is smaller in size, lighter in weight and higher in the energy density than a conventional battery. From these features, the lithium secondary battery is widely used in a commercial field (a power source for personal computers and portable terminals). Further, from the viewpoint of high output density, the lithium secondary battery can be used also as a high-output power source for driving vehicles such as hybrid automobiles (HV).
A lithium secondary battery (typically, a lithium ion battery) like this includes a battery case, an electrode body of a positive electrode and a negative electrode housed in the battery case, and an electrolyte (typically, an electrolyte solution). Each of the positive electrode and negative electrode includes, on a current collector, an electrode mixture layer (specifically, a positive electrode mixture layer and a negative electrode mixture layer) mainly made of an active material capable of reversibly storing and releasing a charge carrier (typically, lithium ions). For example, in a positive electrode of a lithium secondary battery, when a slurry-like (including paste-like, and ink-like) composition (a positive electrode mixture layer-forming slurry) prepared by mixing a positive electrode active material, a high-conductivity material (conductive material) and a binder in an appropriate solvent is coated on a positive electrode current collector, a positive electrode mixture layer is formed.
The conductive material is added to improve the conductivity in a positive electrode mixture layer, and, in a general lithium secondary battery, conductive carbon fine particles (typically, carbon black) are preferably used. However, since the conductive carbon fine particles have a small primary particle size such as several tens nanometers and are strong in cohesion force, it is difficult to uniformly disperse in a solvent. During preparation of a positive electrode mixture layer-forming slurry, by increasing an amount of a solvent used for example, the dispersibility of a carbon powder can be enhanced. However, when an amount of solvent is increased like this, a temperature and/or a time for drying the positive electrode mixture layer-forming slurry become unfavorably high and/or long. As a technology for solving the present problem, Japanese Patent Application Publication No. 10-144302 (JP 10-144302 A) discloses that when a positive electrode mixture layer-forming slurry is prepared, firstly, only a conductive material that is difficult to disperse is dispersed in a solvent with a media disperser (ball mill, for example), followed by mixing and kneading with an active material. According to the method, a positive electrode mixture layer-forming slurry that is free from dispersion irregularity and homogeneous can be prepared.
However, according to the study of the present inventors, when a media disperser such as described in JP No. 10-144302 A is used, since a conductive material, a solvent and a crushing medium (balls in the case of a ball mill, for example) are put together, a particle size distribution of the conductive material after dispersion becomes sharp, and when a positive electrode mixture layer-forming slurry like this is dried, a particle size distribution of the conductive material tended to be eccentrically located. Further, there was a concern that due to a strong shearing action between media, particles are disintegrated to increase the viscosity of a dispersing system or to cause excess dispersion (re-agglomeration of once-dispersed particles) thereof. An increase in the viscosity and the localization of a particle size distribution of the conductive material like this not only deteriorate the work efficiency but also unfavorably induce deterioration of battery performance (an increase in IV resistance, for example). Further, when a media disperser is used, there is a care of wear or contamination of the crushing medium; accordingly, also from the viewpoint of a manufacturing technology, a more excellent method is required.

Method for manufacturing lithium secondary battery


Methods and systems permit rendering a text element formatted using unavailable or restricted fonts. In one embodiment, when producing a document that contains a restricted font, text portions formatted with the restricted font are processed into an alternate representation. A textual representation for the text portions and the additional representation(s) are embedded in a document or container. A unique representation for the restricted font file allows a consuming computing system to attempt to find the restricted font locally. Each textual representation is rendered using its corresponding restricted font, if the restricted font file is found. Otherwise, the additional representation(s) are used.

Font types can include types created by companies known as font foundries. While some foundries allow fonts they have created to be freely distributed or at least to be embedded in documents that are created using the fonts, other foundries restrict what can and cannot be done with a particular font. Generally speaking, there are different levels of restriction that loosely define what one can and cannot do with a particular font. On one level, a font can be completely unrestricted, meaning that one can install it on a client system, distribute it to others for installation, and the like. However, on other levels, there may be various types of restrictions. For example, there are some fonts that carry with them a restriction that they can only be installed on the user's client system if the user is the customer who bought an associated license. In some instances, further restrictions may allow the font to be used for printing, but may not allow the font to be used for anything else, such as doing a print preview. In other instances, embedding the font file associated with a font in a document may be restricted altogether.
These types of restrictions, and others, can greatly inhibit production of a particular document that contains restricted fonts.
Accordingly, this invention arose out of concerns associated with providing systems and methods that enhance production and consumption of documents in view of restricted fonts.

Methods for providing an accurate visual rendition of a text element formatted with an unavailable font


Disclosed in this specification is a golfing glove that is configured to facilitate the proper grip of a golf club handle and a method of using the same. The palmar surface of the glove comprises a first indicator that extends along its width. A second indicator also disposed on the palmar surface. The thumb of the glove has a third indicator. The dorsal surface of the glove has a first elongated indicator aligned with the thumb and a second elongated indicator on the dorsal surface.

It is well recognized in the field of golf that a proper grip is essential for optimal performance. However, many individuals who wish to learn the sport struggle to develop a proper grip. Teaching aids have been developed to assist instructors when teaching new golfers but none of these teaching aids has proven entirely satisfactory. Additionally, many of these aids are prohibited for use during golfing tournaments.
Therefore, an improved teaching aid to promote the proper grip of a golf club is desired.

Teaching aid for properly gripping a golf club and method of using the same


A method of rendering an image includes generating a virtual scene comprising a set of virtual resources, the virtual resources being virtual objects and/or virtual light sources; pre-processing the virtual scene by ray-tracing with respect to a virtual camera position to detect one or more virtual resources not required for ray-tracing rendering of at least an aspect of rendering the image; and rendering the image by a ray-tracing process from the virtual camera position, the ray-tracing process being configured to omit ray-tracing for at least a given aspect of the image, with respect to the one or more virtual resources not required for ray-tracing rendering of at least the given aspect of the image.

This disclosure relates to image rendering using ray-tracing.
Image rendering may be performed using a technique referred to as ray-tracing. This is a technique to generate pixels or samples of an image by tracing so-called rays or light paths and simulating the effects of light encountering objects in the scene being viewed. It can be used as an alternative to other forms of rendering such as so-called scanline rendering.
In a physical reality, light from a light source hits an object and is reflected and/or refracted towards the viewing position such as a user's eye or a camera. In contrast, in rendering systems using ray-tracing, the simulation is performed by emitting virtual or simulated "rays" from the viewing position such as a virtual camera and determining what interactions they undergo when they hit an object or a light source (the latter being either directly or after having hit an object.
The processing requirements of ray-tracing can be high but in some example systems, dedicated ray-tracing hardware can be provided.


A system and method for the wireless transmission of data packets in a code division multiple access communication system wherein one of the code division multiple access channels (PRCH) is used in a time-shared fashion for the transmission of the data packets from several transmitting stations (MSy, MSz) to a receiving station (BS).. A request is sent from a transmitting station (MSy) to the corresponding receiving station (BS) of the communication system indicating the destination address to which data packet(s) are to be routed. PA1 Then, registering the transmitting station (MSy) and assigning an unique virtual connection identifier (VCIy) to it. PA1 Next, the transmitting station (MSy) is attached to the code division multiple access channel (PRCH) used for the transmission of data packets. PA1 Then, listening to the downlink of the code division multiple access channel (PRCH) used for the transmission of data packets until the corresponding receiving station (BS) broadcasts that it will be "idle" such that a random access to the code division multiple access channel (PRCH) used for the transmission of data packets is allowed in the next frame. PA1 Next, the transnmission power of the transmitting station (MSy) is ramped up during the next frame until a certain power level is reached. PA1 The data packet(s) and the virtual connection identifier (VCIy) are transmitted over the uplink of the code division multiple access channel (PRCH) used for the transmission of data packets to the receiving station (BS). PA1 The data packet(s) are routed to the destination address.. Access to the code division multiple access channel (PRCH) used for the transmission of data packets is controller by a multiple access protocol based on carrier sensing and collision detection (CSMA/CD).

Current digital cellular systems such as the Global System for Mobile Communication (GSM) or the Digital Cellular System 1800 (DCS-1800) in Europe, and the Personal Communication Networks (PCN) planned in the U.S. support mainly voice, message, and low-rate connection-oriented data services which are not well suited to support packet-based data communication.
Many mobile computer applications, however, require infrequent transfers of single or multiple data packets over the radio link of the mobile communication system. Some of them, e.g., e-mail, tele-shopping and tele-banking, and vehicle-dispatch or fleet management applications may be well served with a store-and-forward short message service. Others, among them terminal emulation, remote access to local area network (LAN) based servers, or credit-card verification require interactive usage, tolerate little delay, and are characterized by a wide distribution of packet length. There is little doubt that future mobile telecommunication systems such as the Universal Mobile Telecommunication System (UMTS) will have to support such data applications with an efficient packet-data service. In fact, the European Telecommunication Systems Institute (ETSI) is already in the process of defining such a service, called General Packet Radio Service (GPRS), as an extension to the current GSM system.
In the sequel, we will consider connection-less packet-data services for UMTS and PCN systems. In particular, we focus on the UMTS system which was developed in a code division testbed (CODIT) project under the umbrella of the Research in Advanced Communications in Europe (RACE) program. The CODIT system employs spread-spectrum transmission and code division multiple access (CDMA) and supports voice, message, and connection-oriented data services. For more details on the CODIT system please refer to "Design Study for a CDMA Based Third-Generation Mobile Radio System", A. Baier et al., IEEE J. Selected Areas Commun., Vol. 12, 1994, pp. 733-743. CDMA systems are of particular interest because they promise higher capacity and more ease of deployment than competing time-division multiple access (TDMA) systems.
It is an object of the present invention to provide a method and apparatus which enables CDMA-based UMTS and PCN systems to support a connectionless packet-radio service.
It is a further object of the present invention to provide a communication system with added functionalities.

Packet data transmission in code-division multiple access communication systems


There are disclosed a game apparatus, game image preparation method and information storage medium that when a player character moves in a three-dimensional game space, sets a plurality of viewpoints in the field of view in which this character is included and prepares a plurality of two-dimensional images with different contents corresponding to their respective viewpoints.

The present invention relates to a game apparatus, a game image preparation method and an information storage medium for games whose story branches as the game advances.
A game in which a character manipulated by a player (hereinafter referred to as "player character") moves around in the game space, which is a virtual three-dimensional space, and clears a number of events that occur in the meantime is conventionally known. This kind of game is generally called an "action game," and there is a predetermined course, which the player character follows, and various events occur while the player character is tracing the provided course. Moreover, a various ideas are often implemented so that when the player plays this game repeatedly the player can enjoy the game each time by introducing branches to this course and making the content of the game more complicated. For this purpose, each branched course is provided with three-dimensional objects with the greatest possible variations.
Moreover, recently, with increasingly faster processors, etc., techniques of expressing the game space using polygon graphics are generally used. In this case, each three-dimensional object in the game space is configured by polygons and these polygons are accompanied by textures, etc. as the occasion demands. While the player character is following a predetermined course, the viewpoint corresponding to the player also moves simultaneously. Perspective projection conversion is performed based on this viewpoint at a constant time interval (for example, 1/60-second interval), creating a two-dimensional image to be displayed on the display screen.
While it is possible to obtain a more realistic two-dimensional image by creating a game image using the technique of polygon graphics, making complicated figures appear more natural using polygons requires many polygons and textures for each three-dimensional object, thus producing a problem of requiring enormous effort to create data for background scene of the player character. Especially, when there are branches in the story of the game, it is necessary to provide a game space that varies from one course to another at the branch destination, which makes it necessary to create data for background that varies from one course to another and creating the data for background scene requires further effort.

Game apparatus, game image preparation method and information storage medium


An apparatus may comprise a nondestructive evaluation system and a cutting system. The nondestructive evaluation system may be configured to inspect a processed portion of a structure. The nondestructive evaluation system may be configured to determine whether an inconsistency is present in the processed portion. The nondestructive evaluation system may also be configured to generate information about a location of the inconsistency. The cutting system may be configured to cut a number of parts out of the processed portion of the structure in which the inconsistency may be at least substantially excluded from the number of parts.

1. Field
The present disclosure relates generally to manufacturing and, in particular, to a method and apparatus for continuously fabricating composite structures. Still more particularly, the present disclosure relates to a method and apparatus for cutting continuously fabricated composite structures.
2. Background
In manufacturing parts, continuous fabrication systems may be employed to fabricate parts from composite structures. For example, a continuous fabrication system may manufacture a composite structure having a first face sheet and a second face sheet with a core sandwiched between the two fiberglass sheets. As another example, the continuous fabrication system may manufacture the face sheets with carbon sheets instead of fiberglass sheets.
This composite structure may be continuously manufactured in a continuous fabrication system. For example, the composite structure may be fed through the continuous fabrication system. The continuous fabrication system may apply pressure and/or heat to the composite structure to cause the components to cure, bond, attach, and/or adhere to each other. The structure output from the continuous fabrication system may be a processed composite structure.
As a result, the composite structure may be fabricated continuously. For example, without limitation, a completed composite structure may exit the continuous fabrication system, while an uncured and/or unprocessed portion of the composite structure enters the continuous fabrication system for processing.
Parts may be cut out of the processed portion of the composite structure. For example, without limitation, these types of composite structures may be used for floorboards on aircraft, truck cabs, and/or other suitable vehicles. These composite structures also may be used to fabricate other types of parts such as, for example, without limitation, floor beams, longerons, stringers, ribs, skin panels, and other suitable types of parts.
Typically, after the parts are formed from the composite structure, the parts may be inspected to identify inconsistencies. If an inconsistency is present within the part, a determination may be made as to whether the part can be reworked or may be discarded.
This type of manufacturing environment may result in three discreet steps. One step may involve manufacturing the composite structure. A second step may involve cutting parts out of the composite structure, and a third step may involve inspecting the composite structure.
This type of fabrication of parts, however, may result in an increase in the cost of parts when inconsistencies are found and parts are discarded. Further, if the part with the inconsistency can be reworked, the amount of time needed to manufacture the part may be increased.
Therefore, it would be advantageous to have a method and apparatus that takes into account one or more of the issues discussed above, as well as possibly other issues.

Controlling cutting of continuously fabricated composite parts with nondestructive evaluation


A reconfigurable, multi-function data controller for use in a data storage system is selectively adaptable for use as a data channel adapter or a storage device adapter. The controller includes a data channel interface having at least one independent, bi-directional channel interface, for transmitting and receiving commands, data and status with one or more host computers. At least one memory interface transmits and receives commands and data to and from at least one high speed semiconductor memory unit. Additionally, a data storage interface controls and transmits data to and from one or more data storage devices such as a disk drive. A multi-function controller director is coupled to the data channel interface, the at least one memory interface, and the data storage device interface, for directing the reconfigurable multi-function data controller to function as either a data channel adapter or as a storage device adapter in response to selected commands received by the director.

Many large data storage systems such as the IBM 3390 storage system or other compatible systems employ two primary types of controller boards to interface one or more host computers with a plurality of direct access storage devices such as disk drives. The two controllers include a channel adapter, which serves as an interface between the disk storage system and one or more host computers, and a disk adapter which interfaces with one or more data storage devices such as disk drives. The channel adapter receives data and commands over one or more bi-directional channels from the host, and transmits data as well as storage system status information to the host whereas the disk adapter transfers data between the data storage system, cache memory, and the data storage devices.
Although each of these controller boards can be manufactured with little waste of hardware real estate or power consumption to achieve their specific function, each board is thus able to function only as one of the two required controller boards.
There are several negative features, however, of implementing only one function per controller board. These include the cost to the system user of stocking two different kinds of spare controller boards, as well as the manufacturing problems resulting from the requirement to produce, test and inventory two different controller boards. Thus, manufacturing costs as well as the costs of data storage system ownership could be drastically reduced with a single, multi-function controller board.

Reconfigurable, multi-function data storage system controller selectively operable as an input channel adapter and a data storage unit adapter


A target system is dynamically configured to boot from a network connection upon power-up. A portable data loader connected to the target system may receive communications from the target system that a connection has been established. In response, a copy of a target-specific software data loader (SWDL) application may be transmitted from the portable data loader to the target system. The copy of the SWDL application may be stored in volatile memory on the target system and may be executed to support at least one maintenance operation. A user may invoke a maintenance operation by entering a command into the portable data loader. By isolating the data loader application from the operational software stored on the target system, the disclosed methods and apparatus may allow for reduced development and software certification costs for implementing maintenance operations on an embedded system.

Embedded systems are ubiquitously employed in electronic and electromechanical devices to provide one or a few specific functionalities. For example, military and commercial aircraft frequently utilize advanced avionics containing embedded systems such as inertial guidance systems, mission computers, GPS receivers, displays, etc. Each of these target embedded systems may have integrated operational software executing thereon to provide the desired specific functionalities for which the target system was designed. If the operational software is executing on a safety critical target system, such as an automatic flight guidance system, the software must be certified to ensure that operation of the target system meets rigorous legally-mandated safety standards.
As new software is developed or new data becomes available, the integrated operational software loaded on a target system may be updated to provide additional functionality afforded by the new software and/or data. This is typically accomplished by using a set of maintenance features embodied as a target-resident loader application built into the target system (e.g., residing in non-volatile memory on the system), such that execution of these maintenance features allows for software updates to proceed.
In some instances, the BIOS/OS of a target system may be modified to provide dual-boot capabilities to the system so that the target may optionally boot into a standard mode in which its operation software normally operates or a "maintenance" mode in which updates to the software may be performed by a target-resident loader application. Alternatively, maintenance functionality may be directly integrated into the operational software such that updated software and/or data may be provided to the target system when indicated through a user interaction with the target system. Regardless of the method used to provide the software data loader application to the target system, processes associated with the data loader application must be subjected to the same rigorous safety standards as the operational software itself, due to the software data loader application and the operational software being co-resident in non-volatile memory on the target hardware. Without such safety verification, the impact of the software data loader application on the execution of the safety critical operational software is unknown, and therefore not acceptable.

Method and apparatus for updating information on an embedded system


An organic light-emitting diode (OLED) display is disclosed. In one aspect, the OLED display includes a substrate and an active pattern formed over the substrate and including first to fourth regions, the first and fourth regions connected to each other. The display also includes a gate insulation layer formed over the active pattern, and a first gate electrode formed over the gate insulation layer. The first gate electrode, the first region and the second region define a first transistor. The display also includes a second gate electrode formed over the gate insulation layer, and the second gate electrode, the third region and the fourth region define a second transistor. The display also includes a first insulating interlayer formed over the first and second gate electrodes and a conductive pattern formed over the first insulating interlayer. An OLED is configured to receive a driving current from the first transistor.

Field
The described technology generally relates to an organic light-emitting diode display.
Description of the Related Technology
An organic light-emitting diode (OLED) display includes a matrix of pixels each including OLEDs. Light emitted from OLEDs can have a wavelength corresponding to a type of an organic material included in the OLED. For example, OLEDs include different types of organic materials corresponding to red, green or blue colored light. The emitted light is combined so that an image is displayed.
The OLED pixels can be connected to lines or conductive lines. As the resolution of an OLED display increases, a parasitic capacitor can be generated between the lines or the conductive lines of the pixels.


A carrying case for an electronic device, such as a tablet personal computer, is provided, and more specifically a case that allows a user to selectively position a display screen of the tablet personal computer by rotation coupled with angular support. The case is easily adapted for use with many types and models of personal electronic devices and may be utilized to view the display screen in a plurality of orientations.

Various computer companies have developed notebook personal computers ("PCs"), which are similar to large personal digital assistants ("PDAs"), but are about the size of a legal notebook pad. These "tablet" PCs are built in a standard or a convertible form and in a variety of shapes and sizes. For example, Compaq® offers a tablet PC that is similar to a traditional PDA, such that a touch screen is exclusively used to input data into the computer. Conversely, Acer® offers a convertible type of tablet PC that is similar to a notebook computer, such that it is equipped with a keyboard and a screen that swivels and folds over the keyboard in tablet mode. In either form, the tablet PCs have been, and will increasingly become, a useful tool since they are light, store vast quantities of data, and offer the same simplistic features found in PDAs.
Unfortunately, there are some drawbacks to the use of tablet PCs when being viewed by more than one person. More specifically, in order to utilize the larger screen of a tablet PC, the user would have to hold it up or pass it around a meeting or conference room. Thus, some of the benefits of the larger display screen are lost because the user/presenter must hold the tablet PC upright in order for the attendees of the meeting to see the presentation.
Alternatively, the tablet PC may be propped up, but that can lead to other problems such as instability, wherein the tablet PC is more prone to slipping and damage. Further, if a user attempts to prevent slipping by abutting an object against the tablet's lower edge, the view may be partially obstructed. In addition, a propped up tablet PC may not be viewable by every attendee of a meeting because the angle between their line of sight and the plane of the screen may be too shallow. More specifically, as the viewing angle becomes shallow, the image on the screen becomes non-viewable and thus the value of the tablet PC is greatly diminished.
It may also be desirable for the presenter to selectively rotate the screen between portrait view and landscape view, but the problems outlined above still apply. More specifically, a makeshift tilting mechanism may be acceptable for landscape viewing, but may not be ideal for portrait viewing. In addition, it can be easily seen that manual rotation or any unnecessary handling increases the probability of dropping and damaging the expensive tablet PC.
Another drawback to traditional storage cases and support mechanisms is that working on a screen laying flat may be difficult and not ergonomic to the user. In order to write on, or otherwise utilize, a tablet PC it is desirable to prop the tablet PC in an inclined position. Lying a tablet PC flat on a table and writing thereon is not only un-ergonomic, but is more difficult to read because the sight angle is often too shallow. This problem is readily apparent in hand held PDAs, for example the PALM™ handheld, where users hold the device with one hand, tilt the device to a desired angle for viewing and writing, and use the other hand to write. Unfortunately, the size of tablet PCs makes this practice uncomfortable and substantially unmanageable. Alternatively, a user could prop the tablet PC on a desk and use their stomach to brace the lower end. This method is not ergonomic because a user may have to hunch over the tablet PC, which is also impractical for extended periods of use.
Thus, there is a significant need for a carrying case that is adapted to hold and protect a tablet PC, handheld PDA, notebook PC, laptop computer, or other data storage device (hereinafter "electronic device"), that can be easily tilted and selectively rotated between portrait and landscape orientations to facilitate viewing and ergonomic use.

Multi-positionable notebook computer case


A method is provided to functionally select cells with enhanced characteristics relevant to cell engraftment, including both spontaneous migration and directional migration towards specific chemo-attractants. The cells are preferably undifferentiated cells, such as mesenchymal stem cells. The method involves entrapping or encapsulating the cells in a biomaterial barrier, optionally inducing cell migration, and selecting cells that migrated through the barrier. The cells selected by this method have better migratory activities and enhanced in vivo engraftment to injured tissues when they are supplemented systemically.

Cell-based therapy, particularly using undifferentiated cells, e.g., multipotent or pluripotent cells stem cells, presents a promising approach for regenerative medicine and tissue engineering (Short et al. Arch Med. Res. 2003 34(6):565-71, Barrilleaux et al. Tissue Eng. 2006 12(11):3007-19). In particular, bone marrow mesenchymal stem cells (MSCs), or stromal stem cells, have been shown to be beneficial in regenerating tissues of musculoskeletal (Horwitz et al. Nat. Med. 1999 March; 5(3):309-13), cardiovascular (Pittenger et al. Circ Res. 2004 95(1):9-20; Chen et al. Chin Med J (Engl). 2004 117(10):1443-8. Erratum in: Chin Med J (Engl). 2005 118(1):88; Price et al. Int J Cardiol. 2006 111(2):231-9; Wang et al. Crit. Care Med. 2007 35(11):2587-93) and neurological (Helm et al. Neurosurg Focus. 2005 15; 19(6):E13) systems. This is because of their relatively safety and easy accessibility from the donor, genetic stability, and the ability of self-renewal and differentiating into multiple lineages of cells (Pittenger et al. Science 1999 2; 284(5411):143-7; Pittenger et al. Circ Res. 2004 95(1):9-20). They also have the unique immunologically privileged status which can ignore the Human Leukocyte Antigen histocompatibility barrier (Pittenger et al. Circ Res. 2004 95(1):9-20). It is also more socially and ethically acceptable to use MSCs than embryonic stem cells.
Despite the great potential of MSC-based therapies, the functional outcomes of existing MSC therapies have not been satisfactory, at least partly due to the extremely poor engraftment rate (usually <1-2%) of MSCs at the target tissues such as hearts in the treatment of myocardial infarction (Price et al. Int J. Cardiol. 2006 111(2):231-9; Wang et al. Crit. Care Med. 2007 35(11):2587-93) and bones in the treatment of osteogenic imperfecta (Horwitz et al. Nat. Med. 1999 5(3):309-13) upon systemic injection. It is generally believed that the outcomes of MSC therapies can be further enhanced if the engraftment efficiency of human MSCs can be improved. As a result, strategies aimed to enhance the engraftment rate are important to improving the efficacy of MSCs-based therapies.
Local injection of MSCs with and without carriers is able to improve engraftment in the target tissue such as heart and intervertebral disc, but the extent of improvement is less than 5%, which is too low to generate a significant impact. Moreover, the invasiveness associated with the open surgery-based injection into inner organs such as heart and spine, and the inapplicability of local injection in diseases where multiple tissues are involved, such as osteogenic imperfecta and muscle dystrophy, prevents this approach from being widely used in regenerative medicine. Currently, no effective method exists to improve the engraftment rate of systemically supplemented MSCs.
Stem cell engraftment, sometimes used interchangeably with stem cell homing, describes the process of directing undifferentiated cells, such as MSCs, to migrate from the peripheral blood into the damaged tissues (Chamberlain et al. Stem Cells. 2007 25(11):2739-49; Chavakis et al. J Mol Cell Cardiol. 2008 45(4):514-22). The detailed mechanisms of stem cell engraftment are still unclear but directional movement of stem cells towards gradients of chemoattractants and cytokines induced by tissue injuries is known to play an important role (Ponte et al. Stem Cells. 2007 25(7):1737-45; Sordi et al. Blood. 2005 106(2):419-27; Son et al. Stem Cells. 2006 24(5):1254-64; Honczarenko et al. Stem Cells. 2006 24(4):1030-41; Ries et al. Blood. 2007 109(9):4055-63). Among all chemoattractant and receptor pairs, SDF-1 and its specific receptor CXCR4 have been shown to be most important in regulating the migration of hMSCs [Ponte et al. Stem Cells. 2007 25(7):1737-45; Dar et al. Nat. Immunol. 2005 6(10):1038-4; Dar et al. Exp Hematol. 2006 34(8):967-75; Honczarenko et al. Stem Cells. 2006 24(4):1030-41).
Several attempts have been made recently to enhance the responsiveness of MSCs towards specific chemoattractants. In particular, MSCs have been treated with chemoattractants such as SDF-1 (Shi et al. Haematologica. 2007 July; 92(7):897-904; Ponte et al. Stem Cells. 2007 25(7):1737-45), or virally transduced with chemoattractant receptor genes such as CXCR4 (Bhakta et al. Cardiovasc Revasc Med. 2006 7(1):19-24). Both methods upregulate the expression of the chemoattractant receptor on MSCs. A few other approaches include viral transduction of MSCs with anti-apoptotic genes such as Akt and telomerase to promote MSC survival (Seeger et al. Nat Clin Pract Cardiovasc Med. 2007 4 Suppl 1:S110-3) and extrinsic supplementation of chemoattractants such as SDF-1 at the injured target tissues to augment the chemoattractant signal for MSC recruitment at the injury site (Yamaguchi et al. Circulation. 2003 107(9):1322-8). Nevertheless, these approaches also have significant drawbacks such as the long term uncertainty of genetically manipulated cells, the safety issue of virally transduced cells and the poor cost-effectiveness of in vivo supplementation of chemoattractants. More importantly, none of these attempts address the heterogeneity problem of MSCs.
It is therefore an object of the invention to provide methods and compositions to promote or enhance migration, engraftment, or a combination thereof of transplanted cells, such as MSCs.

Methods to enhance cell migration and engraftment


The present invention provides an intraoral quickly disintegrating tablet containing a phosphodiesterase inhibitor having an effect of improving the erectile dysfunction and a method for manufacturing the tablet. The present invention also provides an intraoral quickly disintegrating tablet containing a slightly soluble pharmaceutical agent having an improved solubility and a method for manufacturing the tablet. That is, it is an intraoral quickly disintegrating tablet containing a cyclic GMP phosphodiesterase inhibitor and a saccharide, and a method for manufacturing the tablet. Further, it is a method for manufacturing an intraoral quickly disintegrating tablet, which comprises dissolving a slightly soluble pharmaceutical agent in an organic solvent or an aqueous organic solvent together with a surfactant and/or a water-soluble polymer, coating the solution on a filler or granulating it with a filler to obtain molded products, mixing a saccharide with them, adding an organic solvent, water or an aqueous organic solvent thereto, followed by kneading, and subjecting it to a compression-molding.

The present invention relates to an intraoral quickly disintegrating tablet containing a phosphodiesterase inhibitor having an effect of improving the erectile dysfunction and to a method for manufacturing the tablet.
The present invention also relates to an intraoral quickly disintegrating tablet containing a slightly soluble pharmaceutical agent such as a phosphodiesterase inhibitor having an improved solubility and to a method for manufacturing the tablet.
It is reported in JP-B9-503996 that pyrazonopyrimidinone compounds having an inhibitory action to a cyclic GMP phosphodiesterase type V are useful for the therapy of erectile dysfunction by means of oral administration. Further, 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (general name: sildenafil) belonging to the same classification and being represented by the formula (I) surely shows duration of its pharmaceutical effect at least for two hours when it is orally administered (British J. Urology, 78, 257-261, 1996.) and, therefore, there is a high possibility that they are used for a highly practical drug therapy for erectile dysfunction as a substitute for an injection therapy of papaverine hydrochloride or prostaglandin E1 into corpus cavernosum penis which has been carried out in an urological field. In addition, with regard to a compound having an inhibitory action to a cyclic GMP phosphodiesterase type V, there is disclosed a pyrazolopyrimidinone derivative represented by the formula (II) {1,3-dimethyl-6-(2-propoxy -5-methanesulfonamidophenyl)-1,5-dihydropyrazolo[3,4-d]-pyrimidin-4-one} in JP-A 7-70128 while, in WO 97/03675, there are mentioned a compound represented by the formula (IV) {(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2xe2x80x2, 1xe2x80x2:6,1]pyrido[3,4-b]-indol-1,4-dione)} and a compound represented by the formula (V) {(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2xe2x80x2, 1xe2x80x2:6,1]pyrido[3,4-b]indol-1,4-dione}.
Further, in WO 93/07124, there is mentioned a compound represented by the formula (III) {2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline}. Furthermore, the compounds of a fused pyridazine type represented by the formula (VI) mentioned in JP-A 10-114657 have an inhibitory action to a cyclic GMP phosphodiesterase type V and are useful as therapeutic agents for erectile dysfunction.
It has been said that the number of the latent patients of erectile dysfunction are about 3,000,000 in Japan and are about 20,000,000 in U. S. A. It has been also reported that, while the number of the patients of erectile dysfunction in U. S. A. are only 2-7% of the male population of younger than 50 years age, the rate increases together with aging and 15% of males of fifties and a little over 30% of males of sixties are suffering from this disease. Most of them are derived from organic disorder and, taking the advent of an aging society in near future into consideration, it may be concluded that oral preparations of cyclic GMP phosphodiesterase inhibitors will play a very big role in improving the quality of life (QOL) of the patients suffering from erectile dysfunction.
However, when the conventional oral preparations containing a cyclic GMP phosphodiesterase inhibitor are administered, there is a possibility that, for example, administration of tablets is difficult or that powdery or granular agent adheres in the mouth or comes into artificial teeth whereby a part of the preparation is dropped out since aged people have a low swallowing ability.
When a consideration is made on the standpoint of the aged people as such, there is a very high demand for xe2x80x9ctherapeutic preparations for erectile dysfunction which can be easily taken, easily swollen and easily handledxe2x80x9d which is able to be xe2x80x9cone of the means whereby control of the carnal desire which is the fundamental desire of human being can be embodiedxe2x80x9d. Even in ordinary and healthy adults, therapeutic preparations for erectile dysfunction which can be taken at any place without water greatly contribute to their QOL.
On the other hand, intraoral quickly disintegrating tablets have been known as the tablets which are quickly disintegrated in the mouth and, since they can be easily taken without water, they are recently receiving public attention as a dosage form which is suitable for the people having insufficient swallowing functions such as aged people and small children.
It has been known that the intraoral quickly disintegrating tablets can be prepared, for example, by the use of wet powder. With regard to a method where wet powder is dried without a tableting step whereupon the intraoral quickly disintegrating tablets are prepared, there is disclosed for example in JP-A 5-511543 for xe2x80x9ca solid preparation which is quickly disintegrated in the mouth comprising an active ingredient, a saccharide selected from lactose and/or mannitol and agarxe2x80x9d.
On the other hand, with regard to an intraoral quickly disintegrating tablet prepared by a compression-molding of wet powder filled in a molding machine, there are disclosed, for example, xe2x80x9ca method for the manufacture of an intraoral quickly disintegrating tablet where a mixture containing a pharmaceutical ingredient, a saccharide and water which is in an amount of moisturizing the particle surface of the saccharide is made into a tabletxe2x80x9d in JP-A 5-271054; xe2x80x9can intraoral quickly disintegrating tablet comprising a pharmaceutical agent, a saccharide, a sugar alcohol and a water-soluble polymer and being prepared by moisturizing and moldingxe2x80x9d in JP-A 9-48726; and xe2x80x9ca wet-process tablet where a pharmaceutical agent is mixed with a saccharide, a filler, etc., kneaded after addition of water and/or organic solvent, filled in a mold and subjected to a compression-molding and a method for manufacturing the samexe2x80x9d in JP-A 6-218028. Further, with regard to a method for the molding of an intraoral quickly disintegrating tablet, there is disclosed in JP-A 8-19589 for an invention concerning xe2x80x9ca method for the manufacture of a tablet where wet powder is filled in a hole for molding the tablet and at least one side of the wet powder in the hole is made into a shape of a tablet by means of a metal mold for molding with a film for prevention of adhesion and an apparatus for manufacturing the tabletxe2x80x9d.
However, there has been no report yet for a preparation containing a cyclic GMP phosphodiesterase inhibitor and being able to greatly contribute in such a QOL improvement and for a method of manufacturing such a preparation.
Incidentally, in the case of a slightly soluble pharmaceutical agent, it is not preferred to directly apply the intraoral quickly disintegrating tablet using the above-mentioned known means and the method for manufacturing the tablet. That is because the low solubility of the slightly soluble pharmaceutical agent delays the time for reaching the effective blood level by oral administration and long time is required for achieving the pharmaceutical effect and also because there is a risk that a sufficient pharmaceutical effect is not achieved due to a low bioavailability.
In general, one of the most important factors among various factors affecting the absorption of a pharmaceutical agent via digestive tracts is its solubility and, especially in the case of a slightly soluble pharmaceutical agent, it is quite often that its dissolving rate determines the rate of absorption. Various methods have been known for promoting the solubility of a pharmaceutical agent and they may be roughly classified into the following three. Thus, (1) to increase the surface area of the pharmaceutical particles; (2) to use amorphous or metastable crystals; and (3) to utilize various types of salt or to add a solubilizer. As to the specific means therefor, making the pharmaceutical agent into fine powder, formation of a solvate and adsorption on the surface of a carrier have been known for (1); selection of crystal polymorphism, mixing/pulverization and preparation of a solid dispersion have been known for (2); and preparation of an acidic salt or an alkaline salt, addition of various pH buffers and/or surfactants, etc. have been known for (3) and they are disclosed, for example, in JP-A 59-14446 and JP-A 58-183615.
However, there has been no report yet for an intraoral quickly disintegrating tablet containing a slightly soluble pharmaceutical agent having an improved solubility as such and for a method of manufacturing the tablet. One of the reasons therefor is that it is difficult for satisfying all of the requirements for improving the solubility of the slightly soluble pharmaceutical agent, for a quick disintegration in the mouth and for ensuring a good touch on the tongue upon disintegration. Many of the pharmaceutical ingredients acting as a cyclic GMP phosphodiesterase inhibitor are the compounds having a relatively low solubility and are within a category of the slightly soluble pharmaceutical agents. Especially in the weakly acidic to neutral regions which are the pH of the stomach of the persons of anacidity and the pH ranging from duodenum to small intestine which are the main sites for absorption of the pharmaceutical agent, the solubility significantly lowers. Solubilities at 37 xc2x0 C. in the first disintegration test solution (pH 1.2) and the second disintegration test solution (pH 6.8) according to the Japanese Pharmacopoeia are 2.52 mg/ml and 0.11 mg/ml, respectively for sildenafil (citrate); 0.13 mg/ml and 0.0063 mg/ml, respectively, for 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)-phthalazine hydrochloride which is represented by the formula (IX) among the phthalazine compounds of the formula (VI); and 0.028 mg/ml and 0.0012 mg/ml, respectively, for 4-(3-chloro-4-methoxyphenethyl)-amino-6-cyano-1-(4-hydroxypiperidino)phthalazine hydrochloride represented by the formula (X).
It is worried about that the slight solubility of the cyclic GMP phosphodiesterase inhibitor agent as such may result in a delay of the time reaching the effective blood level, a lowering of the bioavailability and an expansion of the dispersion thereof.
Accordingly, in a cyclic GMP phosphodiesterase inhibitor having such a low solubility, it is desired that the solubility of the effective ingredient in the intraoral quickly disintegrating tablet is improved so that the time for reaching the effective blood level is made shorter and that the absorption is improved so that the bioavailability is improved.
With regard to a preparation containing a cyclic GMP phosphodiesterase inhibitor, there has been a brisk demand for the development of an oral preparation which is able to contribute in the QOL of the patients suffering from erectile dysfunction or, in other words, an oral preparation which can be easily taken by aged people and can be taken without water even by adults having a swallowing ability and a method for manufacturing the preparation.
To be more specific, there has been a demand for the development of an intraoral quickly disintegrating tablet containing a cyclic GMP phosphodiesterase inhibitor having quick disintegrating property and solubility in the mouth and also having a strength for retaining its shape during preservation and a method of manufacturing the tablet.
There has been also a demand for the development of an intraoral quickly disintegrating tablet containing a slightly soluble pharmaceutical agent having quick disintegrating property and solubility in the mouth, showing a good touch on the tongue upon disintegration in the mouth and having a strength for retaining its shape during preservation and a method of manufacturing the tablet. Thus, it is expected that the solubility of the pharmaceutical ingredient in the intraoral quickly disintegrating tablet is improved whereby the time for reaching the effective blood level is made short, the time until expressing the pharmaceutical effect is made short and absorption is improved so that the bioavailability is improved.
However, although there are many aged people among the patients suffering from erectile dysfunction and there have been so many demands for an intraoral quickly disintegrating tablet containing a cyclic GMP phosphodiesterase inhibitor and to a method for manufacturing the tablet, such tablet and method have not been developed yet. Such a situation is the same for an intraoral quickly disintegrating tablet containing a slightly soluble pharmaceutical agent with an improved solubility and a method for manufacturing the tablet as well.
Under such circumstances, the present inventors have carried out an intensive study for investigating an intraoral quickly disintegrating tablet with an excellent disintegrating property containing a cyclic GMP phosphodiesterase inhibitor and a saccharide and a method for manufacturing the tablet and also for an intraoral quickly disintegrating tablet with an excellent solubility containing a slightly soluble pharmaceutical agent and a saccharide and a method for manufacturing the tablet. As a result, it has been found that the aimed object can be achieved by the constitutions as mentioned below whereupon the present invention has been accomplished.
The present invention is an intraoral quickly disintegrating tablet containing a cyclic GMP phosphodiesterase inhibitor and a saccharide.
Further, the present invention is an intraoral quickly disintegrating tablet containing a cyclic GMP phosphodiesterase inhibitor, a saccharide and a binder.
Furthermore, the present invention is an intraoral quickly disintegrating tablet where a cyclic GMP phosphodiesterase inhibitor and a saccharide are mixed, kneaded with an organic solvent, water or an aqueous organic solvent and subjected to a compression-molding and also a method for manufacturing the tablet.
Still further, the present invention is an intraoral quickly disintegrating tablet where a cyclic GMP phosphodiesterase inhibitor and a saccharide are mixed, kneaded with an organic solvent, water or an aqueous organic solvent, filled in a mold and subjected to a compression-molding with a film and also a method for manufacturing the tablet.
The cyclic GMP phosphodiesterase inhibitor covers both that which is slightly soluble and that which is not slightly soluble.
The cyclic GMP phosphodiesterase inhibitor of the present invention may be selected from the group consisting of:
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one represented the formula (I)
1,3-dimethyl-6-(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one represented by the formula (II)
2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline represented by the formula (III)
(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2xe2x80x2, 1xe2x80x2:6,1]pyrido[3,4-b]-indol-1,4-dione represented by the formula (IV)
(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2xe2x80x2, 1xe2x80x2:6,1]pyrido[3,4-b]-indol-1,4-dione shown by the formula (V)
or a pharmacologically acceptable salt thereof.
In addition, the cyclic GMP phosphodiesterase inhibitor may be a compound represented by the following formula (VI) or a pharmacologically acceptable salt thereof
wherein in the formula,
the ring C is an unsaturated 5- or 6-membered ring which may have a hetero atom;
n is 0 or an integer of 1-4;
R1 is a halogen atom, an optionally substituted lower alkyl group, an, optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, nitro group, cyano group, a group represented by the formula xe2x80x94NR2R3, wherein
in the formula, R2 and R3 are the same as or different from each other and each is hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, R2 and R3 may form a ring together with a nitrogen atom bonded thereto, which ring may further have a substituent, a group represented by the formula xe2x80x94Oxe2x80x94R9, wherein
in the formula, R9 is hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, a group represented by the formula xe2x80x94Sxe2x80x94R10, wherein
in the formula, R10 is hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group,
a group represented by the formula (VII):
xe2x80x83wherein in the formula (VII), R11 is hydrogen atom, a lower alkyl group or amino group; and m is 0 or an integer of 1-2, or an optionally protected carboxyl group, and
when n is 2-4, R1 may independently have the above-mentioned substituent;
A is hydrogen atom, a halogen atom, a group represented by the formula xe2x80x94NR4R5, wherein
in the formula, R4 and R5 are the same as or different from each other and each is hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, or R4 and R5 may form a ring together with a nitrogen atom bonded thereto, which ring may further have a substituent,
an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group;
X is a group represented by the formula xe2x80x94NR6xe2x80x94, wherein
in the formula, R6 is hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group,
or a group represented by the formula xe2x80x94Nxe2x95x90;
Y is a group represented by xe2x80x94COxe2x80x94 or a group represented by the formula xe2x80x94C(B)xe2x95x90, wherein
in the formula, B is hydrogen atom, a halogen atom, a formula represented by the formula xe2x80x94NR7R8, wherein in the formula, R7 and R8 may be the same as or different from each other and each is hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, R7 and R8 may form a ring together with a nitrogen atom bonded thereto, which ring may further have a substituent, a group represented by the formula xe2x80x94Oxe2x80x94R12, wherein in the formula, R12 is hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, a group represented by the formulaxe2x80x94Sxe2x80x94R13, wherein in the formula, R13 is hydrogen atom, an optionally substituted lower alkyl group, an acyl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted arylalkyl group or an optionally substituted heteroarylalkyl group; and
the formula (VIII) means a double or single bond, provided that when the ring C is a benzene ring, the case where n is 0 is excluded.
From the above, the compound represented by the formula (VI) may be selected from the group consisting of:
4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperidino)phthalazine hydrochloride represented by the formula (IX)
4-(3-chloro-4-methoxyphenethyl)amino-6-cyano-l-(4-hydroxypiperidino)phthalazine hydrochloride represented by the formula (X)
4-[(3-chloro-4-methoxybenzyl)amino]-1-(2-hydroxy-7-azaspiro[3,5]non-7-yl)-6-phthalazine carbonitrile hydrochloride represented by the formula (XI)
1-(2-hydroxy-7-azaspiro[3,5]non-7-yl)-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazine carbonitrile hydrochloride represented by the formula (XII)
1-[4-fluoro-4-(hydroxymethyl)piperidino]-4-[(4-methoxy-3-methylbenzyl)amino]-6-phthalazine carbonitrile hydrochloride represented by the formula (XIII)
4-[(3-chloro-4-methoxyphenethyl)amino]-1-(2-hydroxy-7-azaspiro[3,5]non-7-yl)-6-phthalazine carbonitrile hydrochloride shown by the formula (XIV)
4-[(3-chloro-4-methoxybenzyl)amino]-1-(3-oxo-2-oxa-8-azaspiro[4,5]decen-8-yl) -6-phthalazine carbonitrile represented by the formula (XV)
Still furthermore, the present invention is a method for the manufacture of an intraoral quickly disintegrating tablet where a slightly soluble pharmaceutical agent is dissolved in an organic solvent or an aqueous organic solvent together with a surfactant and/or a water-soluble polymer, then a saccharide is mixed with a molded product prepared by a coating of a filler or by a granulation together with a filler, an organic solvent, water or an aqueous organic solvent is added thereto and the mixture is kneaded and subjected to a compression-molding. Here, the term xe2x80x9cmolded productxe2x80x9d means granules, fine granules, powder or the like and the molded product may be manufactured using, for example, a fluidized bed granulator, a tumbling granulator, an extrusion granulator or a spray-drying granulator.
Further, the present invention is a method for the manufacture of an intraoral quickly disintegrating tablet where a surfactant and/or a water-soluble polymer are/is added to a slightly soluble pharmaceutical agent followed by mixing, an organic solvent, water or an aqueous organic solvent is added thereto and the mixture is kneaded and subjected to a compression-molding.
The term xe2x80x9cslightly solublexe2x80x9d means that the substance is slightly soluble in water, saliva, gastric juice, intestinal juice, etc., and that can be measured by common tests.
Here, the surfactant and/or the water-soluble polymer play(s) a role of improving the solubility whereby wetting of the slightly soluble pharmaceutical ingredient per se with water is improved. A method for improving the solubility of the pharmaceutical agent in accordance with the present invention is not only able to improve the solubility of the intraoral quickly disintegrating tablet containing the slightly soluble pharmaceutical agent and to ensure its quick disintegration in the mouth but also able to ensure the good touch on the tongue during the disintegration in the mouth.
During the course of the compression-molding in the present invention, it is preferred for keeping the good molding property of the tablet that the powder kneaded with an organic solvent, water or an aqueous organic solvent is filled in a mold and subjected to a compression-molding with a film.
Furthermore, the present invention is an intraoral quickly disintegrating tablet with an improved solubility containing a cyclic GMP phosphodiesterase inhibitor which is a slightly soluble pharmaceutical agent and also is a method for manufacturing the tablet.
Examples of the slightly soluble pharmaceutical agent in the present invention are nifedipine, phenytoin, nitrofurantoin, benoxaprofen, griseofulvin, sulfathiazole, tacrolimus, piroxicam, carbamazepine, phenacetin and cyclic GMP phosphodiesterase inhibitor although the present invention is not limited thereto.
Examples of the cyclic GMP phosphodiesterase inhibitor in the present invention are pyrazonopyrimidinone compounds (JP-B 9-50396) represented by 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (general name: sildenafil) of the formula (I); pyrazolopyrimidinone compounds represented by 1,3-dimethyl-6-(2-propoxy-5-methanesulfonamidophenyl)-1,5-dihydropyrazolo[3,4-d]pyrimidin-4-one of the formula (II) (JP-A 7-70128); (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2xe2x80x2, 1xe2x80x2:6, 1]-pyrido[3,4-b ]indol-1,4-dione) represented by the formula (IV) and (3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2xe2x80x2, 1xe2x80x2:6,1]pyrido[3,4-b ]-indol-1,4-dione represented by the formula (V) (WO 97/03675); 2-(4-carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline represented by the formula (III) (WO 93/07124); a fused pyridazine compound represented by the formula (VI); and a pharmacologically acceptable salt thereof.
Examples of the compound shown by the formula (VI) are 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-l-(4-hydroxypiperidino)phthalazine hydrochloride represented by the formula (IX) (JP-A 8-225541), 4-(3-chloro-4-methoxyphenethyl)amino-6-cyano-1-(4-hydroxypiperidino) -phthalazine hydrochloride represented by the formula (X), 4-[(3-chloro-4-methoxybenzyl)amino]-l-(2-hydroxy-7-azaspiro[3,5]-non-7-yl)-6-phthalazine carbonitrile hydrochloride represented by the formula (XI), 1-(2-hydroxy-7-azaspiro[3,5]non-7-yl)-4-[(4-methoxy-3-methylbenzyl) amino]-6-phthalazine carbonitrile hydrochloride represented by the formula (XII), 1-[4-fluoro-4-(hydroxymethyl)piperidino]-4-[(4-methoxy-3-methylbenzyl) amino]-6-phthalazine carbonitrile hydrochloride shown by the formula (XIII), 4-[(3-chloro-4-methoxyphenethyl)amino]-1-(2-hydroxy-7-azaspiro[3,5]non-7-yl)-6-phthalazine carbonitrile hydrochloride represented by the formula (XIV) and 4-[(3-chloro-4-methoxybenzyl)amino]-1-(3-oxo-2-oxa-8-azaspiro[4,5]dece-8-yl)-6-phthalazine carbonitrile represented by the formula (XV).
However, the cyclic GMP phosphodiesterase inhibitor of the present invention is not limited to those compounds only.
Usually, the compounding ratio of the cyclic GMP phosphodiesterase inhibitor or the slightly soluble pharmaceutical agent in the present invention to 1 part by weight of the tablet is 0.0001-0.4 part by weight, preferably 0.005-0.3 part by weight or, more preferably, 0.01-0.25 part by weight.
An average particle diameter of the cyclic GMP phosphodiesterase inhibitor or the slightly soluble pharmaceutical agent per se is 1-100 xcexcm, preferably 5-70 xcexcm and more preferably, 5-50 xcexcm.
With regard to the saccharide in the present invention, any saccharide may be used so far as it is soluble in water and is stable and its examples are mannitol, sucrose, lactose, trehalose, xylitol, erythritol, glucose, starch and dextrin. In the present invention, each of them may be used solely or two or more thereof may be used jointly.
The compounding ratio of the saccharide in the present invention varies depending upon the type of the cyclic GMP phosphodiesterase inhibitor or the slightly soluble pharmaceutical agent but, usually, it is 2-50 parts by weight, preferably 3-40 parts by weight or, more preferably, 4-30 parts by weight to 1 part by weight of the cyclic GMP phosphodiesterase inhibitor or the slightly soluble pharmaceutical agent.
An average particle size of the saccharide is 1-100 xcexcm, preferably 5-70 xcexcm or, more preferably, 5-50 xcexcm.
The intraoral quickly disintegrating tablet of the present invention may be compounded with a binder if necessary.
Examples of the binder are polyvinylpyrrolidone, Macrogol, hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethycellulose sodium, cellulose acetate phthalate, gum arabic, gelatin, methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol, alpha-starch and pullulan. In the present invention, each of them may be used solely or two or more thereof may be used jointly and the use of polyvinylpyrrolidone is particularly preferred.
The compounding ratio of the binder in the present invention to 1 part by weight of the tablet is usually 0.001-0.1 part by weight or, preferably, 0.005-0.05 part by weight, and that may be appropriately increased or decreased so as to give desired disintegrating degree and hardness. Incidentally, the binder may be added in its powdery form to a mixture of the cyclic GMP phosphodiesterase inhibitor and the saccharide or may be added after dissolving in the organic solvent, pure water or the aqueous organic solvent.
The intraoral quickly disintegrating tablet according to the present invention is a tablet which is quickly disintegrated in the mouth after administration and is able to be easily taken even without water. In addition to the above-mentioned saccharide and binder, the intraoral quickly disintegrating tablet may be compounded with conventionally used filler, lubricant, disintegrating agent, sweetener and/or coloring agent if necessary.
The intraoral quickly disintegrating tablet may be prepared in such a manner that a saccharide and a binder are mixed with a cyclic GMP phosphodiesterase inhibitor, then conventionally used filler, lubricant, sweetener, coloring agent, disintegrating agent, etc. are added thereto if necessary, kneaded with an organic solvent, water or an aqueous organic solvent, filled in a mold and subjected to a compression-molding. The kneading and granulating operations carried out by adding such auxiliary agents for making the preparation and by adding such a solvent may be conducted using the conventionally used apparatus. For example, a fluidized bed granulator, a tumbling granulator, an extrusion granulator or a spray-drying drier may be used.
Examples of the filler are crystalline cellulose, ethylcellulose, dextrin, various kinds of cyclodextrin (xcex1-cyclodextrin, xcex2-cyclodextrin and xcex3-cyclodextrin) as well as derivatives thereof and pullulan.
Examples of the lubricant are magnesium stearate, calcium stearate, stearic acid and talc; examples of the sweetener are aspartame, dipotassiumglycyrrhizinate, white sugar, licorice, saccharin and sodium saccharinate; and examples of the coloring agent are yellow iron sesquioxide, yellow iron oxide, Yellow #4 dye for food, Yellow #5 dye for food, (Yellow #4 dye for food aluminum lake), red iron oxide, iron sesquioxide, Red #2 dye for food, Red #3 dye for food and Red #102 dye for food. In the present invention, each of them may be used solely or two or more thereof may be used jointly.
Examples of the disintegrating agent are light silicic anhydride, crystalline cellulose, cross povidone, lowly substituted hydroxypropyl cellulose, cross carmellose sodium, calcium silicate, magnesium metasilicate aluminate, carboxymethyl cellulose, carboxymethyl cellulose calcium, hydroxypropyl starch, carboxymethyl starch sodium, partially xcex1-starch and sodium alginate. In the present invention, each of them may be used solely or two or more thereof may be used jointly.
In the present invention, an intraoral quickly disintegrating tablet may be manufactured in such a manner that a cyclic GMP phosphodiesterase inhibitor is mixed with a saccharide, a binder is further added thereto if necessary, the mixture is kneaded with an organic solvent, water or an aqueous organic solvent and the resulting wet powder is made into a form of a tablet followed by drying.
In the present invention, an intraoral quickly disintegrating tablet may be manufactured in such a manner that 1) a slightly soluble pharmaceutical agent is dissolved in an organic solvent together with a surfactant and/or a water-soluble polymer, coated on a filler or granulated together with a filler, a saccharide is mixed with the resulting granules, fine granules or powder or that 2) a slightly soluble pharmaceutical agent is mixed with a saccharide and a surfactant and/or a water-soluble polymer, then a binder, a disintegrating agent, a lubricant, a sweetener or a coloring agent is added thereto if necessary and the mixture is kneaded with an organic solvent, water or an aqueous organic solvent and, after that, any of the above-mentioned mixture is filled in a mold followed by subjecting to a compression molding.
Examples of the surfactant used here are sodium lauryl sulfate, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene alkyl phenyl ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitol fatty acid ester and polyoxyethylene glycerol fatty acid ester. In the present invention, each of them may be used solely or two or more thereof may be used jointly.
The compounding ratio of the surfactant in the present invention to 1 part by weight of the slightly soluble pharmaceutical agent is usually 0.0005-0.1 part by weight, preferably 0.001-0.08 parts by weight or, more preferably, 0.001-0.05 parts by weight.
Examples of the water-soluble polymer are hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl cellulose sodium, celluloseacetatephthalate, gumarabic, agar, gelatin, sodium alginate, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol and Macrogol and, in the present invention, each of them may be used solely or two or more thereof may be used jointly.
The compounding ratio of the slightly soluble pharmaceutical agent to the water soluble polymer in the present invention is usually 0.001-0.6 parts by weight or, preferably, 0. 005-0.1 part by weight of the water-soluble polymer to 1 part by weight of the slightly soluble pharmaceutical agent.
Further, the concentration of the water soluble polymer in the solution of the water soluble polymer is usually 0.1-40% by weight or, preferably, 1-20% by weight.
The solution of the water soluble polymer may be any of an aqueous solution, an organic solvent solution and an aqueous organic solvent solution containing the above-mentioned water soluble polymer.
The solvent which is used for the kneading stage in the manufacturing process for the intraoral quickly disintegrating tablet maybe any of an organic solvent, pure water and an aqueous organic solvent. Examples of the organic solvent or of that used for the aqueous organic solvent are ethanol, methanol, propanol and isopropanol and, preferably, ethanol. In the present invention, one of them may be used solely or two or more of them may be used jointly. The preferred compounding ratio of the organic solvent in the aqueous organic solvent is usually 0.05-0.99 parts by weight, more preferably 0.2-0.98 parts by weight or, further preferably, 0.25-0.98 parts by weight to 1 part by weight of the aqueous organic solvent.
In the molding of the wet powder, a lubricant may be applied, if necessary, on upper and lower sides of the kneaded mixture filled therein whereby an adhesion during the compressing step can be prevented but, for the manufacture in a more efficient and easier manner, it is preferred to use a tablet manufacturing apparatus which is disclosed in JP-A 8-19589. Thus, a wet powder is filled in a mold for the tablet molding of the tablet manufacturing apparatus and at least one surface of the wet powder in the mold is molded via an adhesion-preventing film whereby an adhesion of the wet powder to the metal mold for molding can be prevented and a quickly disintegrating tablets are able to be manufactured in an efficient manner.
The pressure applied upon the compression-molding of the wet powder after kneading the mixture or upon tableting via an adhesion-preventing film after filling in a mold in the present invention is usually 2-150 kg/cm2, preferably 2-100 kg/cm2 or, more preferably, 3-50 kg/cm2.
The drying temperature after the compression-molding or the tableting in the present invention is usually 15-80xc2x0 C., preferably 20-75xc2x0 C. or, more preferably, 30-70xc2x0 C.
The tablet hardness of the intraoral quickly disintegrating tablet prepared by the manufacturing method in accordance with the present invention is usually 1-15 kg/cm2 preferably 1.5-10 kg/cm2 or, more preferably, 2-6 kg/cm2. Time for disintegration in the mouth of the intraoral quickly disintegrating tablet is usually 0.05-3 minute(s), preferably 0.05-1 minute or, more preferably, 0.1-0.5 minute.
The water content in the wet powder which is kneaded in the present invention is 0.01-25% by weight, preferably 0.1-20% by weight or, more preferably, 0.1-15% by weight of the kneaded mixture.
The intraoral quickly disintegrating tablet according to the present invention may, for example, be manufactured as follows. Thus, 75 g of sildenafil having the formula (I) which is a cyclic GMP phosphodiesterase inhibitor and 340.8 g of mannitol were well mixed in a mixer. To this mixture was added an aqueous ethanol solution where 4.2 g of polyvinylpyrrolidone K 30 were dissolved in 58.8 g of a 55% ethanol solution followed by kneading for about 3 minutes. After that, the kneaded mixture was subjected to a compression-molding using, for example, a tablet manufacturing apparatus disclosed in JP-A 8-19589 by filling in a mold via a film with a pestle having a diameter of 9.5 mm with a compressing pressure of 35 kg/cm2. The molded product was dried in a drier of 50xc2x0 C. for about 2 hours to manufacture intraoral quickly disintegrating tablets where each tablet (280 mg) contains 50 mg of sildenafil.
Alternatively, 1.5 g of 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-hydroxypiperazino) -phthalazine hydrochloride having the formula (IX) which is a slightly soluble cyclic GMP phosphodiesterase inhibitor and 0.015 g of sodium lauryl sulfate were dissolved in 100 g of a 70% ethanol solution heated at 70xc2x0 C. After that, 40.08 g of mannitol were added thereto and the mixture was well mixed in a mixer, followed by drying to give a powder. To this powder is added an aqueous ethanol solution where 0.42 g of polyvinylpyrrolidone K30 is dissolved in 5.88 g of a 55% ethanol solution, and the mixture is kneaded for about 1 minute. Then the kneaded mixture is subjected to a compression-molding using a compression tester (Shimadzu Autograph) with a compressing pressure of 35 kg/cm2 using a pestle having a diameter of 9.5 mm. The molded product is dried in a drier of 50xc2x0 C. for about 2 hours to manufacture the tablets where each tablet (280 mg) contains 10 mg of the phthalazine compound having the formula (IX).
In accordance with the present invention, it is possible to manufacture an intraoral quickly disintegrating tablet which contains a cyclic GMP phosphodiesterase inhibitor having an improving effect for erectile dysfunction and has quick disintegrating property, solubility and appropriate strength in the mouth.
In accordance with the present invention, it is also possible to manufacture an intraoral quickly disintegrating tablet containing a slightly soluble pharmaceutical agent, being characterized in a quick dissolving in the mouth and having an appropriate strength.
Examples of the such effects will be shown as hereunder.

Tablets immediately disintegrating in the oral cavity