A multilayer optical interference filter having a controlled degree of diffuse reflection over a desired visible wavelength range, includes alternating layers of at least one high refractive index material and at least one low refractive index material, wherein at least one layer of the alternating layers is a light scattering layer comprised of titania which diffusely reflects light over a desired visible wavelength range. The multilayer optical interference filter may be provided by a process including sequentially applying the alternating layers by chemical vapor deposition from respective precursors at temperatures effective to pyrolytically decompose the respective precursors, wherein the precursor of the light scattering layer comprised of titania is at least one branched alkoxide of titania. Vitreous and light transmissive articles, including electric lamps, reflectors, and/or lenses, are provided with a multilayer optical interference filter according to the invention to provide them with a controlled degree of diffuse reflection.

1. FIELD OF THE INVENTION
The present invention relates to a multilayer optical interference filter and its use with light transmissive articles including electric lamps, and, more particularly, to a multilayer optical interference filter having a controlled degree of diffuse reflection with respect to a desired visible wavelength range and its use with light transmissive articles including electric lamps, reflectors and/or lenses.
2. BACKGROUND OF THE ART
Thin film optical interference coatings known as optical interference filters are well known to those skilled in the art and comprise alternating layers of two or more materials of different refractive index. Such coatings are used to selectively reflect and/or transmit light radiation from various portions of the electromagnetic spectrum.
These coatings have been found to be useful to improve the illumination efficacy of incandescent and arc lamps by reflecting infrared radiation emitted back to the filament or arc while transmitting the visible light. This lowers the amount of electrical energy required to be supplied to the filament or arc to maintain its operating temperature.
Such films have also been applied to reflectors in the form of what is known in the art as "cold mirrors" and "hot mirrors". A "cold mirror" is an optical filter which reflects visible light while at the same time permitting longer wavelength infrared energy to pass through the filter. This ensures that the light reflected is much cooler than it would otherwise be if both visible and infrared light were reflected. On the other hand, some reflectors contain a reflecting coating on the inside reflecting surface, such as a coating of aluminum, for reflecting essentially all of the radiation emitted by a lamp filament or arc and projecting it forward of the reflector. In this latter case, the projected light is significantly hotter than that obtained with a cold mirror. Finally, a "hot mirror" is an optical filter which reflects infrared radiation while at the same time permitting shorter wavelength visible light to pass through the filter. One application of hot mirrors in the lamp industry has been to return infrared heat to the filament to increase lamp efficiency.
It is often desirable to diffusely scatter light from an intense source, such as an incandescent filament, by providing the envelope of the incandescent lamp with a light diffusing coating. In reflector lamps provided with lenses or reflectors, stippling has been employed on the lenses and facets have been provided on the reflector in order to diffusely reflect the projected filament images.
One such light diffusive coating is disclosed in U.S. Pat. No. 4,869,927 to Kawakatsu et al., the disclosure of which is incorporated herein by reference. A dip-coating method was used to form a light diffusive coating on a halogen lamp envelope by applying an organo-metallic compound combined with a high boiling point solvent to a base and baking so that the organo-metallic compound decomposes to form a metallic oxide coating including bubbles which scatter light formed by the vaporization of the high boiling point solvent. Such a layer may be used alone or included in a multilayer coating consisting of alternating high refractive index layers made of, for example, titania, and low refractive index layers made of, for example, silica.
U.S. Pat. No. 4,663,557 to Martin, Jr. et al., the disclosure of which is herein incorporated by reference, teaches that an 1100.degree. C. post-deposition heat treatment can transform a specularly reflecting tantala/silica optical interference coating provided on a halogen lamp envelope by vacuum deposition such that it will diffusely reflect visible light while continuing to specularly reflect infrared radiation.
It is therefore an object of the present invention to provide a multilayer optical interference filter having a controlled degree of diffuse reflection with respect to a desired visible wavelength range.
It is another object of the present invention to provide an article which is vitreous and light transmissive with a multilayer optical interference filter having a controlled degree of diffuse reflection over a desired visible wavelength range, such as a reflector or lens, useful, for example, with an electric lamp.
It is yet another object of the present invention to provide an electric lamp including a multilayer optical interference filter having a controlled degree of diffuse reflection over a desired visible wavelength range provided on its lamp envelope and/or on a reflector and/or lens associated with the lamp.

Diffusely reflecting optical interference filters and articles including lamps reflectors and lenses


A hybrid Nyquist thermometer and sigma delta digital to analog converter is presented. The digital input signal is divided into most significant bits and least significant bits. The most significant bits are converted to a thermometer code. A thermometer element array is controlled by the thermometer code. A fractional value is calculated from the least significant bits and used to dither the first unexercised array element in order to get finer resolution with guaranteed monotonicity.

Data converters, both digital-to-analog converters (DAC) and analog-to-digital converters (ADC), are ubiquitous in applications involving digital signal processing of real-world signals such as those found in communication systems, instrumentation, and audio and video processing systems.
Two major issues for DAC design are monotonicity and resolution. Monotonicity means that as the digital value becomes greater, the converted analog value must also become greater. Many DAC building blocks require guaranteed monotonicity with moderate clock rate and moderate design complexity. Examples include a DAC in a digitally controlled oscillator within the PLL loop, or a DAC in a digitally controlled crystal oscillator in an automatic frequency control loop. Matching between different DAC elements is usually required to guarantee monotonic behavior. With the process scaling, the physical size of the DAC elements becomes smaller, and it is therefore more difficult to control the size of the DAC elements, which must be matched to achieve monotonicity. As a result, the physical size of the DAC elements is limited by the matching requirement, thus the DAC does not benefit from the process scaling.
One type of DAC that has guaranteed monotonicity is a thermometer DAC. It is so named because it is similar to a mercury thermometer, where the mercury column always rises to the appropriate temperature and no mercury is present above that temperature. Typically, the input digital signal is binary and the binary code is converted to a thermometer code. The thermometer code is then used to control thermometer elements to generate an analog signal. For a thermometer DAC, elements are all of the same size, so that element matching becomes much simpler than in the binary case. Considering the transfer function, the thermometer converter is monotonic by design, since, when the input value increases, the bits change from 0 to 1 only. The requirement on element matching is also relaxed in the thermometer DAC and monotonicity is guaranteed.
Although the thermometer DAC has guaranteed monotonicity, the maximum resolution n of a thermometer DAC is limited by the capability to implement (2n−1) identical unit devices. Published works show that even with modern technologies, it is very difficult to achieve resolutions higher than 12 bits due to the large amount of thermometer elements and the associated controlled signals. Unfortunately, this resolution is still too low for many applications.
Various methods have been designed to achieve higher resolutions. Each, however, has its limitations. For example, a Nyquist rate DAC has higher design and element matching complexity. A sigma delta DAC requires a much faster clock frequency for over sampling and quantization noise shaping. This element also requires analog filtering.
Typically, to achieve higher resolution, a hybrid scheme of hybrid Nyquist thermometer and sigma delta DAC is used. The resolution can be extended beyond the capability of the thermometer DAC. FIG. 1 illustrates a conventional hybrid Nyquist thermometer and sigma delta DAC. Node 16 outputs analog signals. Input node 2 receives digital input signals with bits. If n bits are all implemented by the thermometer DAC, the generated thermometer code has (2n−1) bits so that (2n−1) elements are required. In the hybrid scheme, the bits are divided into m most significant bits (MSB) named 4n−m through 4n and (n−m) least significant bits (LSB) named 40 through 4n−m−1. The m most significant bits 4n−m through 4n are converted to thermometer code by a thermometer decoder 6. The thermometer code is used to control an element array 10 to generate an analog signal.
It is noticed that the value represented by the (n−m) LSB is always smaller than the value represented by the last bit of the MSB, or the bit 4n−m. Therefore, the value represented by the (n−m) least significant bits can be calculated as a fraction of the "whole" value of an element. The fractional value is typically converted to the analog signal by dithering a fixed and pre-determined thermometer element 14 that is substantially identical to other elements. Dithering the element 14 to a fractional value C means that when converting a fraction value, the element is turned on C of the time, and off (1−C) of the time, therefore, the analog output can have a value that is only a fraction of the "whole" value of an element.
The advantage of the hybrid DAC can be explained using an example. Assume a DAC with 14 bits resolution is desired. Since the 14 bits thermometer DAC requires 214−1, or 16,383 elements, it is difficult to implement the DAC as a thermometer DAC. However, it is common to implement a 10 bits thermometer DAC. Therefore, the 14 bits digital signal can be divided as 10 bits MSB and 4 bits LSB. The smallest value represented by the MSB is 16, or binary 10000, while the greatest value represented by the 4 bits LSB is 15, or binary 1111. Therefore, the LSB always represents a fractional value of the MSB. For example, 00,0000,0001,0011 can be represented as 00,0000,0001+ 3/16. Converting such a digital signal to analog means turning on one thermometer element and dithering another element 3/16 of the time. With the hybrid scheme, only 210, or 1024 thermometer elements are required. Therefore, the production cost is lowered and design is less complex.
Typically, dithering is performed on one dedicated element 14, as illustrated in FIG. 1. This requires element 14 to have very good matching with the other elements 101 through 102^m−1 in the DAC to guarantee monotonicity. However, the fractional value of the dithered element may not be smaller than the "whole" value of the thermometer DAC element, thus creating a non-monotonic DAC transfer function. In order to guarantee monotonicity, the matching between this dithered element and the rest of the DAC element needs to be so good that under all thinkable process, voltage, and temperature conditions, non-monotonicity will not occur. This matching requirement demands a certain physical size of DAC elements and prevents the DAC from having the benefit of process scaling.

Guaranteed monotonic digital to analog converter


A tape drive apparatus enables cleaning of a read/write converter head when a tape cartridge is inserted or removed, without interfering with or moving the tape. The tape drive apparatus has a loading mechanism for transferring an inserted tape cartridge to a predetermined position in the apparatus, and a head cleaning unit that can move between a cleaning position in contact with the converter head and a withdrawn position isolated from the converter head. The head cleaning unit moves between the withdrawn position and the cleaning position in synchronization with the transfer operation of the loading mechanism, when there is not tape over the head. In this manner, the head cleaning operation does not interfere with or move the tape.

The present invention relates to a tape drive apparatus, and more particularly, to a head cleaning mechanism for a tape drive.
Japanese Published Unexamined Patent application JP11-296827A2 discloses a typical tape drive apparatus provided with a cleaning mechanism for a read/write converter head. In this related art, the tape drive apparatus has a converter head for reading the data tape of a loaded tape cartridge, and a cleaning device for cleaning the converter head. The cleaning device has a support arm and a rotatable cleaning brush at the end of the arm. When necessary, the converter head can be cleaned by inserting the support arm between the data tape and converter head.
However, this related art has the following problems. First, since the converter head is cleaned when the data tape is in contact with the converter head, the data tape is pushed out away from the head by the cleaning brush. This places excessive tension on the data tape, resulting in a problem from the point of view of data protection.
Moreover, an independent drive source is required to drive the support arm and thereby the cost is increased. In addition, the internal space available for the other mechanisms in the tape drive is reduced to provide installation space for the drive source. Thereby, the entire structure is more complicated and the cost is also increased due to the complication of the structure.
The present invention has been proposed to eliminate the problems explained above and therefore an object of the present invention is to provide a tape drive apparatus of simplified structure enabling cleaning of the converter head at predetermined times.
In the present invention, a head cleaning unit for cleaning a read/write converter head moves to a withdrawn position from a cleaning position when a loading mechanism is driven toward a loading side (set position side) of a tape cartridge, that is, as a tape cartridge is loaded. The head cleaning unit moves to the cleaning position from the withdrawn position in synchronization with the loading mechanism moving toward the tape cartridge eject side of the loading mechanism, that is, when the tape cartridge is ejected.
The withdrawn position may be set within the apparatus so that it is located at an area away from the running path of the data tape, that is, where interference with the data tape is not generated. Moreover, the moving path of the head cleaning unit may be linear or curved.
With cooperation between the operation of the tape cartridge and operation of the head cleaning unit, automatic cleaning of the converter head can be realized through insertion and removal of the tape cartridge, without any action by a user. Therefore, the converter head can always be maintained in the clean condition, improving reliability of read and write operations. Moreover, since the cleaning operation of the converter head is performed after the loading mechanism has exhausted the tape cartridge, namely when the data tape is not present, the data tape is not damaged.
In known devices the movable part of the loading mechanism, for example, is monitored with a sensor and the head cleaning unit is driven with an adequate actuator in order to synchronize the operation of the head cleaning unit with that of the loading mechanism. With the present invention, it is no longer required to additionally provide such a sensor or actuator for head cleaning purposes, and the structure may be simplified. Manufacturing cost can also be reduced because displacement of the movable part of the loading mechanism can adequately be transferred to the head cleaning unit via the transferring part. In this case, the transfer part is adequate when it can transfer the movement of the movable part of the loading mechanism to the head cleaning part. This can be accomplished by adjusting the moving stroke between the cleaning position and withdrawn position of the head cleaning unit.


A closed compressor is provided with a flexible oil fence, of which a fixed portion as one end is fixed onto an upper surface of a cylinder between a shaft and a cylinder head and a free end as the other end extends toward an upper inner surface of a closed container. According to this configuration, a collision sound can be prevented from being generated even when the oil fence collides with the upper inner surface of the closed container and hot oil can be prevented from flowing along a surface of suction muffler.

In the related art, as one of these types of closed compressors, there is a closed compressor in which oil sucked up from a lower end of a crank shaft is ejected from an upper end, falls onto a rib formed on a block, and becomes an oil droplet (for example, refer to PTL 1).
FIG. 13 is a side sectional view of a closed electric compressor in the related art which is described in PTL 1 and FIG. 14 is a sectional view taken along arrow 14-14 in FIG. 13.
As illustrated in FIGS. 13 and 14, the closed electric compressor in the related art includes closed container 1, oil 2 that is reserved in a bottom portion of closed container 1, compression unit 3 that is disposed on an upper side, and electric unit 4 that is disposed on a lower side. Compression unit 3 includes crank shaft 5, of which lower end 6 is immersed in oil 2 and which is rotated by electric unit 4, and block 8 that rotatably supports crank shaft 5. In addition, block 8 is provided with cylinder 9 including an open end and rib 12 for fixing cylinder head 13 that serves as a lid of the open end of cylinder 9 and suction muffler 14 is disposed below rib 12 of block 8.

Closed compressor and refrigeration device using the same

PANASONIC APPLIANCES REFRIGERATION DEVICES SINGAPORE


A silver halide emulsion is described, which contains tabular silver halide grains having {100} faces as the parallel two major planes, having an aspect ratio of 2 or more and having a mean silver chloride content of 50 mol % or more, in an amount of 50% or more of the total projected area of all the silver halide grains therein, and which is spectrally sensitized with a particular trimethine dye of formula (I). A photographic material having the emulsion has a high sensitivity and good storability and can be processed rapidly.

A demand for rapid processing of silver halide photographic material is increasing in these days. In general, silver bromide is used in photographic materials. However, for rapid processing of photographic materials, it is desirable that silver chloride is used in them. However, silver chloride grains have problems in that they weakly adsorb dyes, that they are weakly sensitized with spectral sensitizing dyes and that the storability of the grains themselves is poor. Accordingly, the use of tabular grains having large surface area and having large adsorptive capacity of dye in silver halide photographic materials is advantageous. As tabular grain, tabular grains having {111} faces as the major planes are generally used in view of the easiness of the production, the photographic sensitivity and the sharpness of the materials. However, the tabular grains having {111} faces as the major planes have a problem in that their intrinsic desensitization due to dyes is great.
According to A. Mignot, E. Francois & M. Catinat, "Cristaux de Rbomure D'argent Plats, Limites par des Faces (100) et non Macles", Journal of Crystal Growth 123 (1974), 207-213, it is reported that they have observed tabular silver bromide crystals with {100} faces having square or rectangular major planes.
According to the disclosure of U.S. Pat. No. 4,063,951, the tabular grains with {100} crystalline faces are formed from monodisperse seed grains and they are ripened in the presence of ammonia to have a mean aspect ratio falling within the range between 1.5 and 7. U.S. Pat. No. 4,386,156 mentions a method for producing emulsions of tabular silver bromide grains, in which seed grains are ripened in the absence of a non-halide complexing agent for silver ions, to form tabular silver bromide grains having a mean aspect ratio of 8 or more. A method for producing tabular grains having a high silver chloride content is illustrated in EP-A-534395.
The inventors of the present invention tried to use the tabular grains having {100} faces as the major planes as silver halide grains to confirm that such tabular grains cannot meet practical use because they particularly weakly adsorb dyes.
Accordingly, the inventors have conducted extensive investigations in order to obtain dyes excellent in adsorption on tabular silver halide grains having {100} faces as the major planes, and have achieved the present invention.

Silver halide emulsion and silver halide photographic material using the same


Disclosed is a federated architecture and system which are extensible and flexible for integrated access to heterogeneous DataBase Management Systems (DBMS) dispersed over a long haul network, allowing transparent access to a wide variety of DBMS while maintaining the local autonomy of the underlying DBMS. In addition the system can run on top of different hardware, operating systems, network communications, and DBMS. The system can include new target DBMS with minimum changes and is not limited to integrate relational DBMS, but also to integrate legacy DBMS such as hierarchial or network DBMS, spatial information or text retrieval systems.

1. Field of the Invention
This invention relates in general to an architecture and method useful in computer data networks, and, more particularly, to a federated (global) architecture and system which are extensible and flexible for providing users with transparent integrated access to heterogeneous DataBase Management Systems (DBMS) dispersed over a long haul network.
2. Description of the Related Art
During the past decade, large scale organizations and environments have initially adopted heterogeneous and incompatible information systems in an uncoordinated way; independent of each other and without consideration that one day they may need to be integrated. As a result, information systems have become more and more complex, and are characterized by several types of heterogeneity. For example, different DataBase Management Systems (DBMS) models may be used to represent data, such as the hierarchical, network, and relational models. Aside from databases, many software systems (such as spreadsheets, multi-media databases and knowledge bases) store other types of data, each with its own data model. Furthermore, the same data may be seen by various users at different levels of abstraction. Because of such differences, users find it difficult to understand the meaning of all the types of data presented to them. Analysts, operators and current data processing technology are not able to organize, process and intelligently analyze these diverse and massive quantities of information. Their inefficiency often results in late reports to decision makers, missed intelligence opportunities and unexploited data.
One of the needs is to access and manage existing and new earth science data. The data is been collected and stored within a number of different DBMSs and image files for the purpose of monitoring global earth processes. The earth science data are collected by different information systems including data concerning: climate, land, ocean, etc., which are composed of relational databases, images, and files. These systems were designed independently and operate in completely different ways as to how the data are stored and accessed. Moreover, they are tailored to different hardware platforms. So, in order to access the data, the users must learn how to access different systems. This increases training costs and reduces user productivity. In addition, the majority of users do not have the level of computer science expertise necessary to learn the different individual systems within a short period of time, thus discouraging them from accessing dispersed data, or in some instances from even knowing what data are available for their use.
The same problems occur in the Computer Integrated Manufacturing (CIM) environment. CIM is a very complex network of physical activities, decision making and information flow. Most manufacturing facilities contain independently designed and dispersed information bases. In such an environment, improvement in manufacturing productivity can be obtained by providing timely access to all essential data, local or distributed. Present CIM systems lack a federated, i.e., global, database which contains information required for all phases of manufacturing, that is, design, process, assembly and inspection. Usually, manufacturing processes are treated independently from the other phases. This is undesirable in the sense that data or knowledge from one process is not available for use by another. There is need to integrate data so that they can be made globally available to the users and processes of a CIM system.
In conclusion, there is an urgent need to integrate these dispersed data to provide uniform access to the data, to maintain integrity of the data, and to control its access and use. Rather than requiring users to learn a variety of interfaces in order to access different databases, it is preferable that a single interface be made available which provides access to each of the DBMSs and supports queries which reference data managed by more than one information system.
Past and current research and development in distributed databases allows integrated access by providing a homogenizing layer on top of the underlying information systems (UISs). Common approaches for supporting this layer focus on defining a single uniform database language and data model that can accommodate all features of the UISs. The two main approaches are known as view integration and multi-database language.
The view integration approach advocates the use of a relational, an Object-Oriented (OO), or a logic model both for defining views (virtual or snapshot) on the schemas of more than one target database and for formulating queries against the views. The view integration approach is one mechanism for homogenizing the schema incompatibilities of the UISs. In this framework, all UISs are converted to the equivalent schemas in the standard relational, 00, or logical data model. The choice of the uniform data model is based on its expressiveness, its representation power and its supported environment. This technique is very powerful from the user's point of view. It insulates the user from the design and changes of the underlying Information Management System (IMS). Thus, it allows the user to spend more time in an application environment. However, the view integration approach has a limited applicability (low degree of heterogeneity) because there are many situations when the semantics of the data are deeply dependent on the way in which the applications manipulate it, and are only partially expressed by the schema. Many recent applications in areas where traditional DBMSs are not usable fall into this situation (multi-media applications involving Text, Graphics and Images are typical examples). In addition, there are no available tools to semi-automate the building and the maintenance of the unified view which is vital to the success of this technique.
In the multi-database language approach, a user, or application, must understand the contents of each UIS in order to access the shared information and to resolve conflicts of facts in a manner particular to each application. There is no global schema to provide advice about the meta-data. Ease of maintenance and ability to deal with inconsistent databases make this approach very attractive. The major drawback of this approach is that the burden of understanding the underlying IMSs lies on the user. Accordingly, there is a tradeoff between this multi-database language approach and the view integration approach discussed above. This invention will address the deficiencies suffered from the above two approaches.

Apparatus and method for providing users with transparent integrated access to heterogeneous database management systems


A universal portable support platform for a ladder base is formed from a plurality of interfitting elements capable of left and right interconnections so that a horizontal support can be located selectively adjacent an elevated work site. Adjustment means are provided to level the horizontal support, regardless of the angulation of the ladder base.

1. Field of the Invention
This invention relates to a support platform to be attached to a ladder and by means of which the user may have access to a variety of articles and/or containers carried on the platform, in conducting work tasks while mounted on the ladder.
2. Description of the Prior Art
Work tasks are frequently performed while mounted on a ladder designed to place the user at an elevated position above a support surface, such as ground level. However, the user, or worker, while so mounted may require access to a variety of tools and/or containers. For example, if the task relates to painting, the user may want to have within easy access one or more paint brushes, sometimes of more than one size, and the user may also desire access to a can of paint or a paint tray for use with a brush applicator, as well as wiping cloths, scrapers and possibly other tools and appliances.
Other work tasks may require that the worker have access to various tools of different descriptions as may be used in construction and repair. Generally, such needs are satisfied by the improvisational use of hooks and other suspension devices by means of which the articles are suspended from one of the rungs or steps of the ladder. With such jury rigged arrangements, access to the tools is limited and convenience is lost.
Further, if the prior art devices are designed for rung-type ladders, they cannot be effectively used with ladders of the slat-type steps, and vice versa. Again, different ladders fold out to different degrees of angulation, and if the prior art device is of a suspension type, it may not hang properly and is thus incapable of properly supporting the article for maximum utilization by the worker.
Prior art hook devices are also incapable of providing a flat platform surface for the proper support of utilitarian articles. If, perchance, something resembling a flat surface is provided, it may not be disposed in a horizontal plane, and is incapable of proper adjustment for optimum placement adjacent the work site.
Some ladders are provided with a utility platform at the level of the top rung or top step of the ladder. When the legs are folded out, the platform is folded down and is permanently locked in place. It cannot be moved laterally or vertically and is generally of a limited size dictated by the spacing dimension between the legs and the rungs of the ladder.

Universally adjustable support platform for ladders


A production apparatus of hypochlorite solution includes an electrolytic cell having a housing the interior of which is subdivided by a partition membrane to form therein anode and cathode chambers, and positive and negative electrodes respectively disposed within the anode and cathode chambers and opposed to each other through the partition membrane, wherein the positive and negative electrodes are applied with DC voltage to effect electrolysis of chloride solution such as sodium chloride solution or potassium chloride solution supplied into both the anode and cathode chambers, and wherein acid water and alkaline water respectively produced in the anode and cathode chambers are mixed to produce hypochlorite solution. In the production apparatus of hypochlorite solution, the anode chamber of the electrolytic cell is supplied with chloride solution through a supply conduit connected thereto, while the cathode chamber of the electrolytic cell is supplied with city service water through a supply conduit connected thereto.

1. Field of the Invention
The present invention relates to a production apparatus of hypochlorite solution in which acid water and alkaline water are produced by electrolysis of chloride solution such as sodium chloride solution, potassium chloride solution or the like and mixed to produce hypochlorite solution.
2. Discussion of the Prior Art
Disclosed in Japanese Patent Publication No. 4-42077 is a production apparatus of this kind which includes an electrolytic cell having a housing the interior of which is subdivided by a partition membrane to form anode and cathode chambers, and positive and negative electrodes respectively disposed within the anode and cathode chambers and opposed to each other through the partition membrane. In the electrolytic cell, the positive and negative electrodes are applied with DC voltage to effect electrolysis of chloride solution supplied into both the anode and cathode chambers, and acid water and alkaline water produced by electrolysis of the chloride solution respectively in the anode and cathode chambers are mixed to produce hypochlorite solution.
In the electrolytic cell, the chloride solution supplied into the cathode chamber is uselessly consumed for production of the hypochlorite solution, resulting in an increase of the production cost of hypochlorite solution.
It is, therefore, a primary object of the present invention to provide a production apparatus of hypochlorite solution capable of producing the hypochlorite solution at a low cost without useless consumption of the chloride solution.
According to the present invention, the object is attained by providing a production apparatus of hypochlorite solution which includes an electrolytic cell having a housing the interior of which is subdivided by a partition membrane to form anode and cathode chambers, and positive and negative electrodes respectively disposed within the anode and cathode chambers and opposed to each other through the partition membrane, wherein the positive and negative electrodes are applied with DC voltage to effect electrolysis of chloride solution supplied into both the anode and cathode chambers, wherein acid water and alkaline water produced by electrolysis of the chloride solution respectively in the anode and cathode chambers are mixed to produce hypochlorite solution, and wherein the anode chamber of the electrolytic cell is supplied with chloride solution through a supply conduit connected thereto, while the cathode chamber of the electrolytic cell is supplied with city service water through a supply conduit connected thereto.
As in the production apparatus of hypochlorite solution, the cathode chamber R2 is supplied with the city service water for production of hypochlorite solution in the electrolytic cell, the consumption amount of salt for preparation of the chloride solution can be reduced less than that in the conventional apparatus in which the chloride solution is supplied into both the anode and cathode chambers. This is useful to reduce the production cost of hypochlorite solution. In the case that the anode chamber is supplied with chloride solution of high concentration, a conductive degree of ion can be increased, and the voltage between the electrodes can be lowered.
In a practical embodiment of the present invention, it is preferable that flow restriction means is provided in the anode chamber to restrict an amount of the chloride solution supplied into the anode chamber. In such an embodiment, an amount of non-electrolyzed chloride solution can be decreased to enhance the electrolysis efficiency of the chloride solution.
It is also preferable that a discharge conduit is connected to the cathode chamber of the electrolytic cell to discharge alkaline water from the cathode chamber therethrough and that flow quantity control means is provided on the partition membrane to adjust an amount of the alkaline water flowing into the anode chamber from the cathode chamber therethrough. In such an embodiment, the mixture ratio of acid water and alkaline water produced respectively in the anode chamber and cathode chamber can be adjusted by operation of the flow quantity control means to adjust the concentration and pH of hypochlorite solution.
Alternatively, in a practical embodiment of the present invention, a discharge conduit is connected to the cathode chamber of the electrolytic cell to discharge therethrough alkaline water from the cathode chamber, a flow quantity control valve is disposed within the discharge conduit to adjust an amount of alkaline water discharged from the cathode chamber through the discharge conduit, and a check valve is provided on the partition membrane to interrupt the flow of alkaline water from the cathode chamber into the anode chamber. In such an embodiment, the amount of alkaline water discharged from the cathode chamber through the discharge conduit can be adjusted by the flow quantity control valve so that the flow amount of alkaline water from the cathode chamber into the anode chamber is controlled to adjust the mixture ratio of alkaline water and acid water thereby to adjust the concentration and pH of the hypochlorite solution in desired values. In addition, the flow of acid water from the anode chamber into the cathode chamber is interrupted by the check valve to restrain deterioration of the negative electrode in the cathode chamber caused by reaction with hydrogen ion contained in the acid water.

Production apparatus of hypochlorite solution


A method for producing an activated carbon sheet having high electrolyte impregnation capacity and high mechanical strength is provided. The method for producing an activated carbon sheet includes a sheet preparation step of preparing a sheet including an activated carbon, an electrically conductive carbon material, and a fibrous fluorocarbon resin binder, which fluorocarbon resin is polytetrafluoroethylene and/or modified polytetrafluoroethylene; and a light irradiation step of performing light irradiation of at least one side of the sheet such that the cumulative irradiation dose on the sheet surface is 50 to 1000 mJ/cm2.

An electric double layer capacitor (hereinafter referred to as "EDLC") is a condenser utilizing physical accumulation of charge based on an electric double layer, and has a number of advantages over chemical-reaction-based secondary batteries, such as an ability of high-output quick charge/discharge, and non-polluting properties. It is expected that electric double layer capacitors will be applicable to various uses, including use of compact electric double layer capacitors for electronic devices, and use of large electric double layer capacitors in automobile batteries. An electrode film for an EDLC is usually comprises a powder electrode such as an activated carbon; an electrically conductive material; a binder such as a fluorocarbon resin; and the like (e.g., JP 2004-2105 A).
The performance of an EDLC is influenced by the amount of an electrolyte impregnated in this electrode film. JP 4-47449 B describes destroying of the surface of a sheet-like electrode, especially a dense and smooth layer containing a large amount of a tetrafluoroethylene resin (polytetrafluoroethylene; hereinafter referred to as "PTFE"), to provide the surface of the sheet-like electrode with flaws in order to improve the electrolyte impregnation capacity of the sheet-like electrode.
However, use of this technique may cause the sheet-like electrode to be destroyed, leading to powder falling from the sheet-like electrode and shape changes (thickness, density, and the like), resulting in deterioration of the electric stability of the sheet-like electrode or an EDLC using the sheet-like electrode.
On the other hand, there is a known technique in which an electrode film for an EDLC is irradiated with an electromagnetic wave to improve its properties. For example, JP 2008-205275 A describes that, by irradiating an activated carbon as a material for an EDLC electrode with an electromagnetic wave in an atmosphere of hydrogen or the like, an oxygen-containing functional group present on the surface of the activated carbon is released, and that the thus produced material for an EDLC electrode can be used for production of a high-capacity EDLC having stable performance.
JP 2002-237434 A describes a technique in which, in order to solve problems caused by attachment, in a layer-forming manner, of a binder such as PVDF on the surface of an activated carbon during production of an electrode body, an electrode functional material prepared by kneading a powder electrode material, a binder, and a solvent is applied to a surface of a metal foil, and is dried, and then dried material is irradiated with laser to remove the layer of the binder attached, in a layer-forming manner, to the surface of the active substance, while maintaining the binder function of each particle. The document mentions an excimer laser as an example of this laser.
However, the techniques disclosed in JP 2008-205275 A and JP 2002-237434 A are not intended for improvement of the electrolyte impregnation capacity of an EDLC electrode film.

Method for producing activated carbon sheet and method for improving impregnation of activated carbon sheet with electrolyte solution


An intelligent gate drive unit and related method for controlling one or more semiconductor switches of one or more power modules, the intelligent gate drive unit comprises at least a gate driver and an analog measuring circuit, wherein the gate driver facilitates control of the one or more semiconductor switches and wherein the analog measuring circuit facilitates measuring the switch voltage when the one or more semiconductor switches are in a conducting mode.

Power modules are known in the art and used as switches or rectifiers in power electronic circuits for controlling the power flow from a generator of a renewable power generating unit to the electrical grid.
The application in which the power modules are used may produces power and the closer to design limits the more power may be produced.
Such power modules can be protected by the way they are controlled i.e. most likely the lifetime of a power module which has been controlled close to its design limits are shorter than a power module which has been controlled according to an operation margin or safety margin which is lower than the design limit. In other words overload capabilities are limited by predefined current-time pattern which means large operation margin for overload.
International patent application WO 99/19974 A2 describes a power application circuit utilizes microelectromechanical (MEM) switches to reduce power loss in energy conversion equipment having a gate drive controlling the MEM switch.
In addition the state of the art includes the following patent applications. US patent application US 2010/0066337 A1 describes a power converter comprising a controller configured to estimate a terminal voltage of the power converter. European patent application EP2469710 A1 describes a power switch current estimator at a gate driver. US patent application US 2011/0058296 A1 describes a method of detecting a fault condition of a load device controlling the amount of power delivered to an electrical load. International patent application WO 2006/102930 A1 describes an electronic switch circuit connected to control means, a detector sensing current flow at terminals of the electronic switch and means for monitoring offset error of the detector.

Gate drive unit with analog measuring circuit


A method and apparatus for collecting fibrous material (14) comprises distributing the fibrous material (14) onto a collection surface (18) to form a pack (20), and intercepting a portion of the fibrous material (14) during formation of the pack (20) with a plurality of spikes (24) extending from the collection surface (18). The spikes (24) partially penetrate the pack (20) and retain the intercepted fibrous material (14) in the upper portion (27) of the insulation pack (20).

A common method of collecting fibrous material, particularly fibrous mineral material, involves distributing the fibrous material onto a collecting surface to form an insulation pack. The fibers can be collected as a pack on an endless belt positioned beneath the fiber distributing apparatus, and the pack can be built up continuously on the moving belt. Such fiber collection apparatus can be combined with an exhaust fan positioned to draw gases through the belt and thereby force the fibrous material toward the belt to form the pack. Apparatus for forming packs, such as insulation packs as thick as 3 inches or more, can use a series of fiber distributing means. The exhaust fans associated with such apparatus for producing relatively thick insulation packs can have an extremely strong suction effect on the fibrous material, since the manufacture of thicker insulation packs generally requires stronger suction fans.
A common problem with such apparatus is that the fan pulls the initially deposited fibers onto the belt so that the bottom layer of the insulation pack is denser than the upper portions. It is believed that the greater the final thickness of the insulation pack, the greater is the density variation from the bottom to the top of the pack. The fact that the bottom portion of the insulation pack is of greater density than the upper portion of the pack is undesirable in that the greater density portion does not compensate for the increased material usage by providing an equivalent increased thermal insulative value.


A method and apparatus for performing endolaser microsurgery is disclosed, the apparatus including a laser delivery system coupled to a probe capable of transmitting the laser energy through a suitable medium such as sapphire. The probe includes a coaxial canal for aspiration of ablated tissue and/or fluids. The method involves steps of ablating tissue by laser and aspirating the ablated tissue and/or fluids, the method being useful for sclerostomy, vitrectomy and as a substitute for ultrasonic phacoemulsification among others.

Recent advances in technology and techniques have made the use of lasers in 1 procedures increasingly common. The precision attained through the use of lasers and laser equipment has particular advantages in microsurgical procedures which were formerly not possible using conventional instruments. As the field has developed, however, some of the techniques which are now in use and which are theoretically sound have led to previously unforeseen problems.
As an example, the conventional surgical procedure to produce a new outflow path for the aqueous humor in glaucoma patients has consisted of several steps, making the operation complicated and relatively traumatic. As a result, the procedure often fails due to wound healing, which closes the newly formed opening by scarring. Several authors have thus investigated the use of lasers to simplify this procedure and to reduce trauma:
Q-switched YAG laser pulses have been delivered by means of a specially designed mirror-contact lens across the anterior chamber and aimed at the sclera anteriorly to the trabeculum meshwork. The difficulties and uncertainties of this method are: (1) The high energies (50 mj and more) per pulse cause hemorrhages of the iris due to the shock waves. Consequently, the iris base is preoperatively photocoagulated. (2) Special precautions are necessary to not inadvertently penetrate the conjunctiva. The energy per pulse can be reduced by injecting silver oxide intralimbally, which complicates the procedure.
CW-YAG laser was delivered through a sapphire contact probe, which was inserted through the cornea opposite to the area of trabecular meshwork to be perforated. The tissue touched by the sapphire tip was vaporized. There are essentially two difficulties anticipated: (1) Inserting the sapphire tip is a invasive procedure, and (2) using a cw: YAG laser causes more thermal damage to remaining tissue than by using short pulsed lasers, thus increasing wound healing reactions and lowering the success rate.
CW ultraviolet laser had been delivered through an optical fiber in a similar way as the sapphire tip described above. The anticipated problems are the same.
308 nm wavelength pulses from an excimer laser had been delivered through an optical fiber the same way as above. Beside the same disadvantage of being an invasive procedure, this wavelength causes high risks because of its phototoxic effects to retina and lens, and because of potential carcinogenic effects.
A 193 nm excimer had been used ab externo after removal of the conjunctiva. This wavelength cannot be transmitted through an optical fiber.


A low dose antidiabetic pharmaceutical formulation is provided, especially adapted for treating Type II diabetes in drug naive patients, which includes a combination of metformin (employed in a reduced amount (less than 800 mg metformin per day) compared to that employed in generally accepted medical practice) and at least one other antidiabetic agent such as a sulfonyl urea, for example, glyburide, which combination provides at least about substantially equivalent efficacy in treating diabetes in drug naive patients, as do antidiabetic formulations containing metformin employed in dosages prescribed in generally accepted medical practice for first line therapy in treating diabetes, but with substantially reduced side effects, such as hypoglycemia and/or gastrointestinal distress. A method for treating diabetes in drug naive human patients is also provided employing the above formulation to reduce insulin resistance and/or post-prandial glucose excursion and/or hemoglobin 1Ac, and/or increase post-prandial insulin, thereby treating the diabetes.

The present invention relates to a low dose pharmaceutical formulation for treating type 2 diabetes in drug naive patients, which includes metformin (preferably employed in reduced amounts compared to that employed in generally accepted medical practice) and another antidiabetic agent such as a sulfonyl urea, for example, glyburide, which formulation has at least substantially equivalent efficacy in treating type 2 diabetes as compared to prior art antidiabetic formulations containing metformin, but with substantially reduced side effects, and to a method for treating diabetes employing such formulations.
The biguanide antihyperglycemic agent metformin disclosed in U.S. Pat. No. 3,174,901 is currently marketed in the U.S. in the form of its hydrochloride salt (Glucophage(copyright)), Bristol-Myers Squibb Company).
The diagnosis and management of type 2 diabetes mellitus is rapidly undergoing progressive changes. It is now widely accepted that glycemic control makes a difference. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. The diagnosis of diabetes has undergone significant changes as evidenced by the new ADA diagnostic and classification guidelines. Oral therapeutic options for the treatment of type 2 diabetes mellitus, until recently, have been severely limited. Prior to 1995, sulfonyl ureas had been the mainstay of oral diabetes agents in the United States. Sulfonyl ureas target one mechanism of hyperglycemia by augmenting insulin secretion from the beta cell. Since 1995, three new classes of agents have been added to the anti-diabetes armamentarium for the management of hyperglycemia. Metformin, a biguanide, targets additional mechanisms of hyperglycemia by inhibiting hepatic glucose production and enhancing peripheral glucose uptake and thereby reduce insulin resistance; thiazolidinediones such as troglitazone, rosiglitazone and pioglitazone decrease peripheral insulin resistance; and alpha-glucosidase inhibitors such as acarbose and miglitol help control postprandial glucose excursion by delaying absorption of dietary carbohydrate. These agents are all indicated as monotherapy and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate.
In 1995, metformin was added to sulfonyl urea therapy n patients who had not achieved glycemic control with sulfonyl urea monotherapy and the two agents were found to have a remarkable effect on glycemic control or lowering of hemoglobin-A1c. The different mechanisms of action in targeting hyperglycemia are complimentary and make combination use attractive and a rational course of action. Prescription data reveals approximately 60% of metformin use is in combination with a sulfonyl urea.
Examples of combinations of metformin and the sulfonyl urea glyburide (also referred to as glibenclamide) are disclosed in the following references.
(1) WO 97/17975 published May 22, 1997, (Barelli et al, Istituto Gentili S.P.A.) (hereinafter Barelli et al) discloses a combination of glibenclamide and metformin in a 1:100 weight ratio, so as to allow a daily dosage of 15 mg glibenclamide and 1500 mg metformin, used for the onset of diabetes to the most severe cases, particular in cases of secondary failure to a combination of glibenclamide-metformin HCl in a weight ratio higher than 1:100.
(2) Vigneri et al, Treatment of NIDDM Patients with Secondary Failure to Glyburide: Comparison of the Addition of Either Metformin or Bed-Time NPH Insulin to Glyburide, Diabete and Metabolisme, 1991, 17, 232-234, disclose use of a combination of 1.5 g/day metformin and 15 mg/day glyburide to treat NIDDM patients with secondary failure to 15 mg/day glyburide.
(3) Higginbotham et al, Double-Blind Trial of Metformin in the Therapy of Non-Ketotic Diabetes, The Medical Journal of Australia, Aug. 11, 1979, 154-156, discloses treatment of diabetic patients, who were already receiving from 10 mg to 20 mg per day of glibenclamide, with 500 mg metformin twice a day. Higginbotham et al conclude xe2x80x9cthat in selected diabetics whose condition is inadequately controlled with sulphonylurea therapy, significant improvement in diabetic control can be obtained by the addition of metformin in a low dose of 500 mg twice a day.xe2x80x9d
(4) U.S. application Ser. No. 09/353,141, filed Jul. 14, 1999 (based on European application No. 98401781.4, filed Jul. 15, 1998) discloses formulations containing metformin and glyburide where the glyburide is of a particular particle size as described hereinafter.
References which disclose combinations of metformin and glipizide include the following:
(1) Combination of glipizide/metformin treatment reduces low density lipoprotein binding to arterial proteglycans in DIDDM, Edwards et al, Diabetes, (46, Suppl. 1, 45A, 1997).
(2) Combination of glipizide/metformin normalizes glucose and improves insulin sensitivity in hyperinsulinemia moderately well controlled. Cefalu et al, Diabetes, (45, Suppl. 2, 201A, 1996).
(3) Effects of combination of glipizide/metformin treatment on oxidizability of LDL in NIDDM, Crouse et al, Circulation, (94, No. 8, Suppl., 1508, 1996).
(4) Insulin sensitivity is improved after glipizide monotherapy and combination with metformin, Cefalu et al, Diabetologia, (39, Suppl. 1, A231, 1996).
(5) Combined Metforminxe2x80x94Sulfonyl urea Treatment of Patients with NIDDM in Fair to Poor Glycemic Control, Reaven et al, J. Clin. Endocrinol. Metab. (74, No. 5, 1020-26, 1992).
(6) Combination of Glipizide/Metformin Treatment in NIDDM, Hollenbeck et al, Diabetes, (39, Suppl. 1, 108A, 1990).
(7) Oral Antidiabetic Combination Therapy with Sulfonyl ureas and Metformin, Haupt et al, Med. Welt. (40, No. 5, 118-23, 1989).
(8) Variation of the lipemic pattern in diabetic subjects after treatment with a combination of glipizide and metformin, Ferlito et al, PROGR. MED. (Roma) 31/6 (289-301) 1975.
(9) Results with a combination of glipizide and dimethylbiguanide in 40 cases of diabetes, Parodi et al, GAZZ. MED. ITAL. 132/5 (226-235) 1973.
Other combinations of metformin and another antidiabetic agent are disclosed in the following references.
(1) U.S. Pat. No. 5,631,224 to Efendic et al discloses a combination of metformin with GLP-1(7-36) amide or GLP-1(7-37) or a fragment thereof.
(2) WO 98/57634 (SKB) discloses a method for treating diabetes employing a combination of a thiazolidenedione and metformin. The thiazolidenedione may be troglitazone, ciglitazone, pioglitazone or englitazone, and may be employed in dosages of 2 to 12 mg per day while the metformin may be employed in daily dosages xe2x80x9cof up to 3000 mg per day, in unit doses of 500 mg (for example, 2 to 3 times per day) or 850 mg (2 times per day), one example of a dosage for metformin is 500 mg building to 5 times per day.xe2x80x9d
(3) EP 0749751A2 (Takeda) discloses a combination of a thiazolidenedione insulin sensitivity enhancer (such as pioglitazone) and metformin.
None of the above references suggests employing diabetic combinations containing metformin for first line treatment of drug naive patients.
Several fixed combinations of metformin and glyburide (glibenclamide) are presently being marketed outside the U.S. These include (1) combinations of 400 mg metformin/2.5 mg glibenclamide (Boehringer""s Bi-Euglucon in Argentina, and Bi-Euglicon M in Italy; Guidotti/Menarini""s Glibomet in the Dominican Republic and Italy; HMR""s Normell in Greece and Hoechst""s Suguan-M in Italy; Sun Pharma""s Glucored in India; Monsanto""s (Searle""s) Benclamet in India; Guidotti""s Globate in Liban; Berlin Chemie/Menarini""s Glibomet in the Slovak Rep., and Roche""s Bi-Euglucon in Uruguay); (2) combinations of 500 mg metformin/5 mg glibenclamide (Sun Pharma""s Glucored in India; Monsanto""s (Searle""s) Benclamet in India, USV""s Duotrol in India; and Lakeside""s (Roche) Bi-Euglucon M5 in Mexico); (3) combinations of 500 mg metformin/2.5 mg glibenclamide (Molteni""s Glucomide in Italy, Lakeside""s (Roche) Bi-Euglucon M in Mexico and Szabo""s Dublex in Uruguay); and (4) 1 g metformin/5 mg glibenclamide (Silanes Sil-Norboral in Mexico).
The labelling for Glucophage(copyright) (Bristol-Myers Squibb""s metformin), in the Physicians"" Desk Reference 1999, under xe2x80x9cIndications and Usexe2x80x9d, indicates that Glucophage may be used concomitantly with a sulfonylurea. It is further indicated under xe2x80x9cDosage and Administrationxe2x80x9d xe2x80x9cConcomitant Glucophage and Oral Sulfonylurea Therapyxe2x80x9d that xe2x80x9cIf patients have not responded to four weeks of the maximum dose of Glucophage monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing Glucophage at the maximum dose . . . With concomitant Glucophase and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the maximum effective dose of each drug to achieve this goal.xe2x80x9d The recommended dosing schedule for Glucophage is a starting dose of 500 mg twice a day or 850 mg once a day with dosage increases in increments of 500 mg weekly or 850 mg every 2 weeks up to a total of 2000 mg per day.
Package inserts for Bi-Euglucon M and Suguan M in Italy (400 mg metformin/2.5 mg glibenclamide) indicate that these drug combinations are used in cases of primary or secondary resistance to sulfonyl ureas [that is as second or third line therapy] and that a dosage of xc2xd tablet per day increasing xc2xd tablet at a time according to glycemic variations up to 4 tablets per day are employed.
Package inserts for Glibomet (400 mg metformin/2.5 mg glibenclamide) and Glucomide (500 mg metformin/2.5 mg glibenclamide) in Italy indicate that these drug combinations are used for treating type 2 diabetes which is non-controllable or cannot be controlled with only diet or with diet and sulfonyl urea [that is as first line therapy of second line therapy].
The package insert for Glibomet in Italy indicates a daily dosage of 2 tablets, that is 800 mg metformin and 5 mg glibenclamide, up to 2 grams metformin. The package insert for Glucomide in Italy indicates a daily dosage of 2 capsules, that is 1000 mg metformin up to 2 grams metformin, and 5 mg glibenclamide.
In accordance with the present invention, a low dose pharmaceutical formulation is provided which includes a combination of metformin and at least one other antidiabetic agent, which preferably is glyburide, which combination provides at least substantially equivalent efficacy in treating diabetes in drug naive patients (in first line therapy) as do combinations of metformin and the other antidiabetic agent employed in substantially higher dosages as prescribed in generally accepted medical practice for first line therapy in treating diabetes. However, use of the low dose pharmaceutical formulation of the invention results in substantially reduced side effects as compared to the same combination employed in the higher doses as generally prescribed.
It is to be understood that the low dose formulation of the invention will include a xe2x80x9clow dosexe2x80x9d of at least one of the active antidiabetes drug components, that is a lower dosage than the dosage for such drug prescribed in generally accepted medical practice in first line therapy of treating diabetes. Thus, the above low dose pharmaceutical formulation will include a low dose of metformin as defined hereinafter, or a low dose of other antidiabetic agent as defined hereinafter, or a low dose of each of metformin and other antidiabetic agent as defined hereinafter.
In accordance with the present invention, efficacy in first line therapy in treating diabetes in drug naive patients is achieved employing the low dose pharmaceutical formulation of the invention wherein the daily dosage of the metformin may be employed in a daily dosage prescribed in generally accepted medical practice for first line therapy in treating diabetes, and is preferably within the range which comprises a starting daily dosage as low as about one-fifth of the starting daily dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes, up to a daily maintenance dosage of about two-thirds of the daily maintenance dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes.
The low dose pharmaceutical formulation of the invention will more preferably contain metformin where the daily dosage of the metformin is within the range which comprises a starting daily dosage as low as about 25% up to about 60% of the starting daily dosage of metformin employed in generally accepted medical practice for first line therapy for treating diabetes, up to a daily maintenance dosage of from about 40 to about 60% of the maintenance dosage employed in generally accepted medical practice for first line therapy for treating diabetes.
Thus, in effect, the low dose pharmaceutical formulation of the invention will be employed in first line therapy in a daily dosage to provide less than about 800 mg metformin per day, preferably no more than about 750 mg metformin per day, more preferably no more than about 600 mg metformin per day, and a minimum (starting dosage) of about 160 to about 225 mg per day, in single or divided doses of one to four tablets daily.
The other antidiabetic agent (which preferably is a sulfonyl urea, preferably glyburide) may be employed in a daily dosage prescribed in generally accepted medical practice for first line therapy in treating diabetes, and is preferably employed in a daily dosage within the range which comprises a starting daily dosage as low as about one-tenth of the starting daily dosage of other antidiabetic agent employed in generally accepted medical practice for first line therapy for treating diabetes, up to a daily maintenance dosage of about two-thirds of the daily maintenance dosage of other antidiabetic agent employed in generally accepted medical practice for first line therapy for treating diabetes.
The other antidiabetic agent will preferably be employed in a daily dosage within the range which comprises a starting daily dosage as low as about 20% up to about 60% of the starting daily dosage of such other antidiabetic agent employed in generally accepted medical practice for first line therapy for treating diabetes, up to a daily maintenance dosage of about 40 to about 60% of the daily maintenance dosage of such other antidiabetic agent employed in generally accepted medical practice for first line therapy for treating diabetes.
The above daily dosage of the other antidiabetic agnet (which preferably is glyburide) includes starting daily dosages of such antidiabetic agent (for example 0.1 to 1.5 mg glyburide) up to a maximum maintenance daily dosage as prescribed in generally accepted medical practice for first line therapy in treating diabetes. In the case of glyburide, the daily dosage will preferably be up to two-thirds the daily dosage as prescribed in generally accepted medical practice for first line therapy in treating diabetes that is up to about 4.5 mg, preferably up to about 3.75 mg glyburide, per day, in single or divided doses of one to four tablets daily.
The term xe2x80x9clow dose combinationxe2x80x9d, xe2x80x9clow dose formulationxe2x80x9d or xe2x80x9clow dose pharmaceutical formulationxe2x80x9d as employed herein, in a preferred formulation of the invention, refers to a formulation which includes metformin in a starting daily dosage of as low as about one-fifth the starting daily dosage of metformin prescribed in generally accepted medical practice for first line therapy in treating diabetes up to about two-thirds the maintenance daily dosage of metformin prescribed in generally accepted medical practice for first line therapy in treating diabetes. The above daily dosage of metformin incudes starting daily dosages of metformin (for example as low as 160 mg) and dosages of metformin titrated up to a maximum maintenance dosage of less than about 800 mg metformin per day, preferably less than about 750 mg per day; and other antidiabetic agent employed in amounts set out herein.
Until now, combinations of metformin and another antidiabetic drug, for example, a sulfonyl urea, such as glyburide, have normally been used with few exceptions, as second line therapy in treating type 2 diabetes. Generally accepted medical practice daily dosages for such second line therapy employing fixed combinations of metformin and glyburide range from 3 to 4 tablets containing 400 to 500 mg metformin and 2 to 2.5 mg glyburide, or about 1200 to 2000 mg metformin and 6 to 10 mg glyburide, daily.
As indicated above with respect to Glibomet and Glucomide (fixed combinations of metformin and glyburide) marketed in Italy, these combinations may be employed as first line therapy (drug naive patients) in a daily dosage of 800 to 1000 mg up to 2 grams metformin and 5 mg glibenclamide (glyburide). This daily dosage is referred to herein as xe2x80x9cdosages prescribed in generally accepted medical practice for first line therapy in treating diabetesxe2x80x9d or as dosages of xe2x80x9cprior art combinationsxe2x80x9d or xe2x80x9cprior art daily dosages.xe2x80x9d
The above dosages may be included within the term xe2x80x9cdosages as prescribed in generally accepted medical practice for first line therapy in treating diabetes.xe2x80x9d
As indicated above with respect to Boehringer""s Bi-Euglucon M and Hoechst""s Suguan M (fixed combinations of metformin and glibenclamide) marketed in Italy, these combinations are employed as second line therapy in a daily dosage starting at xc2xd tablet, that is, 200 mg metformin and 1.25 mg glibenclamide. The initial or starting low doses are employed to determine if the patient can tolerate the drugs and these doses are gradually titrated upwardly xc2xd tablet at a time up to 4 tablets per day until an efficacious dosage is achieved. The initial or starting daily dosage of xc2xd tablet or 200 mg metformin and 1.25 mg glibenclamide is not considered by Boehringer and Hoechst and physicians prescribing these drugs as xe2x80x9cdosages as prescribed in generally accepted medical practice for treating diabetes.xe2x80x9d
Surprisingly, it has been found that use of the combination of metformin and glyburide in accordance with the present invention affords the following benefits. The low dose metformin is an insulin sensitizer and decreases insulin resistance at the liver, muscle and pancreas. The low dose metformin-glyburide combination acts on the pancreas as a glucose sensitizer; it decreases glucose toxicity at the pancreas and improves function of the pancreas.
In addition, in accordance with the present invention, a method is provided for treating diabetes, especially type 2 diabetes, in a drug naive human patient, which includes the step of administering to a drug naive human patient in need of treatment, as first line therapy, a therapeutically effective low dose pharmaceutical formulation of the invention which includes a combination of metformin and at least one other antidiabetic agent (preferably glyburide), in dosages as described herein, which combination provides at least substantially equivalent efficacy in treating diabetes in drug naive patients as do combinations of metformin and said other antidiabetic agent employed in dosages prescribed in generally accepted medical practice for first line therapy treating diabetes, but with substantially reduced side effects.
In addition, in accordance with the present invention, a method is provided for decreasing fasting plasma glucose, decreasing insulin resistance, decreasing hemoglobin A1c, increasing post-prandial insulin and/or decreasing post-prandial glucose excursion in a human diabetic patient, which includes the step of administering to a human patient the low dose pharmaceutical formulation of the invention which includes a combination of metformin/other antidiabetic agent, preferably glyburide. It is preferred that the low dose pharmaceutical formulation be administered as first line therapy and that the human patient be a drug naive patient.
In carrying out the method of the invention employing the preferred low dose pharmaceutical formulation of the invention containing metformin and glyburide, to treat drug naive patients for diabetes, it has been found that the efficacy in treating drug naive patients is at least substantially equivalent and incidence of side effects (gastrointestinal side effects and hypoglycemia) is surprisingly significantly and substantially reduced as compared to patients on prior art daily dosages of metformin and glyburide (that is in dosages prescribed in generally accepted medical practice for treating diabetes). Thus, while efficacy in treating drug naive patients as measured by decrease in hemoglobin A1c from baseline over time, decrease in fasting plasma glucose (FPG), increase in post-prandial insulin levels, and decrease in post-prandial glucose (PPG) excursion, are essentially substantially equivalent in the above-described patients when employing the low dose pharmaceutical formulation of the invention and the prior art daily dosages or prior art combinations, incidence of hypoglycemia in drug naive patients treated with prior art daily dosages is more than 3 times greater than in patients treated with the low dose pharmaceutical formulation of the invention, and incidence of gastrointestinal side effects in drug naive patients treated with prior art daily dosages is more than 20% greater than patients treated with the low dose pharmaceutical formulation of the invention.
Preferred daily dosages of a combination of metformin and glyburide will be in the range from about 175 to about 600 mg metformin, more preferably from about 200 to about 500 mg metformin, still more preferably from about 250 to about 400 mg metformin, and from about 0.5 to about 4.5 mg glyburide, preferably from about 0.625 to about 3.75 mg glyburide, and more preferably from about 1 to about 1.5 mg glyburide.
The term xe2x80x9cdiabetesxe2x80x9d as employed herein, refers to type 2 (or Type II) diabetes or non-insulin dependent diabetes mellitus (NIDDM).
The term xe2x80x9cmetforminxe2x80x9d as employed herein refers to metformin or a pharmaceutically acceptable salt thereof such as the hydrochloride salt, the metformin (2:1) fumarate salt, and the metformin (2:1) succinate salt as disclosed in U.S. application Ser. No. 09/262,526 filed Mar. 4, 1999, the hydrobromide salt, the p-chlorophenoxy acetate or the embonate, and other known metformin salts of mono and dibasic carboxylic acids including those disclosed in U.S. Pat. No. 3,174,901, all of which salts are collectively referred to as metformin. It is preferred that the metformin employed herein be the metformin hydrochloride salt, namely, that marketed as Glucophage(copyright) (trademark of Bristol-Myers Squibb Company).
The term xe2x80x9csubstantially reduced side effectsxe2x80x9d as employed herein refers to reduced incidence of hypoglycemia and gastrointestinal adverse events including diarrhea, nausea/vomiting and/or abdominal pain, occurring with use of the low dose pharmaceutical formulation of the invention in drug naive patients as compared to patients on the same active components in the pharmaceutical formulation of the invention but at higher dosages as prescribed in generally accepted medical practice for treating diabetes.
The term xe2x80x9cat least substantially equivalent efficacyxe2x80x9d in treating type 2 diabetes as employed herein refers to the effectiveness of the low dose pharmaceutical formulation of the invention in treating drug naive patients to reduce and/or maintain hemoglobin A1c (glycosylated hemoglobin) at 7% or less, to decrease insulin resistance (by increasing post-prandial insulin level) and/or to decrease post-prandial glucose (PPG) excursion, as compared to patients treated with the same active components in the pharmaceutical formulation of the invention but at higher dosages as prescribed in generally accepted medical practice for treating diabetes.
The term xe2x80x9cpost-prandial excursionxe2x80x9d as employed herein refers to the difference between post-prandial glucose (PPG) and fasting plasma glucose (FPG).
The low dose pharmaceutical formulation of the invention will contain metformin used in combination with another antidiabetic agent (also referred to herein as xe2x80x9canother antihyperglycemic agentxe2x80x9d) which may be administered orally in the same dosage form or in separate oral dosage forms or by injection.
The other antidiabetic agent may be one or more of the following: a sulfonyl urea, a glucosidase inhibitor, a thiazolidinedione, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin, a PPAR xcex1/xcex3 dual agonist, a meglitinide, and/or an aP2 inhibitor.
It is believed that the use of metformin in combination with another antidiabetic agent in accordance with the present invention produces antihyperglycemic results greater than that possible from each of these medicaments alone and greater than the combined additive anti-hyperglycemic effects produced by these medicaments.
The other antidiabetic agent will preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Pat. No. 4,379,785), glipyride, glipizide, gliclazide or chlorpropamide, and/or other known sulfonyl ureas or other antihyperglycemic agents which act on the ATP-dependent channel of the xcex2-cells, with glyburide being most preferred. The sulfonyl urea may be administered in the same oral dosage form with metformin or a separate oral dosage form.
Metformin will be employed in a weight ratio to the sulfonyl urea in the range from about 1000:1 to about 10:1, preferably from about 400:1 to about 100:1, more preferably from about 250:1 to about 150:1, and optimally about 200:1.
The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769), vaglibose, miglitol (disclosed in U.S. Pat. No. 4,639,436), which may be administered in a separate oral dosage form or the same dosage form with metformin.
Metformin will be employed in a weight ratio to the glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 50:1.
The other antidiabetic agent may be a meglitinide, for example, repaglinide (Prondin(copyright), NovoNordisk) or nataglinide (Starlex(copyright), Novartis), which may be administered in a separate oral dosage form or the same oral dosage form with metformin.
Metformin will be employed in a weight ratio to the meglitinide within the range of from about 0.01 to about 500:1, preferably from about 0.5:1 to about 300:1.
Metformin may be employed in combination with a thiazolidinedione oral antidiabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as troglitazone (Warner-Labert""s Rezulin(copyright), disclosed in U.S. Pat. No. 4,572,912), rosiglitazone (SKB-Avandia(copyright)), pioglitazone (Takeda-Lilly-Actos(copyright)), Mitsubishi""s MCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Welcome""s GL-262570, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer), which may be administered in a separate oral dosage form or the same oral dosage form with metformin.
Metformin will be employed in a weight ratio to the thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
The thiazolidinedione in amounts of less than about 150 mg oral antidiabetic agent may be incorporated in a single tablet with metformin.
The other antidiabetic agent may be an aP2 inhibitor such as disclosed in U.S. Provisional Applications No. 60/100,677 filed Sep. 17, 1998, and No. 60/127,745 filed Apr. 5, 1999, the disclosures of which are incorporated herein by reference. Doses employed are as set out in the above applications.
Metformin will be employed in a weight ratio to the aP2 inhibitor in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 2:1. The aP2 inhibitor and metformin may be incorporated in the same or separate dosage forms.
Metformin may also be employed in combination with a non-oral antihyperglycemic agent such as insulin or with glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference), which may be administered via injection, or by transdermal or buccal devices.
Where present, the sulfonyl urea, such as glyburide, glimepiride, glipyride, glipizide, chlorpropamide or gliclazide, the thiazolidenedione, such as troglitazone, rosiglitazone or pioglitazone, the glucosidase inhibitor acarbose or miglitol, the meglitinide such as repaglinide or nataglinide, or insulin may be employed in formulations as described above and in formulations, amounts and dosing as indicated in the Physicians"" Desk Reference.
Where present, GLP-1 peptides may be administered in oral buccal formulations, by nasal administration or parenterally as described in U.S. Pat. Nos. 5,346,701 (TheraTech), 5,614,492 and 5,631,224 which are incorporated herein by reference.
Metformin may be employed in combination with another antidiabetic agent which may be a PPAR xcex1/xcex3 dual agonist such as an N-benzyldioxothiazolidylbenzamide derivative such as disclosed in WO 96/38428 such as 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide (KRP-297), WO 98/05531 (Ligand Pharmaceuticals, Inc.) which discloses 2-(4-[2,4-difluorophenyl]-1-heptylureido)ethyl]phenoxy)-2methylbutyric acid, and WO 97/25042 and WO96/04260 (SKB) which disclose benzoxazole and pyridine derivatives of the structure
or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein R0 represents 2-benzoxazolyl or 2-pyridyl and R1 represents CH2OCH3 or CF3, such as (S) -3-[4-[2-[N-(2-benzoxazolyl) -N-methylamino)ethoxy]phenyl]-2-(2-methoxy-ethoxy)propanoic acid; or (S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]-ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid; or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof. Dosages employed are as set out in the above references.
Metformin will be employed in a weight ratio to the PPAR xcex1/xcex3 dual agonist within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
Where metformin is employed in combination with the PPAR xcex1/xcex3 dual agonist, the combination may be employed in an oral dosage form such as a tablet or capsule as will be apparent to one skilled in the art.
Preferred are low dose combinations of metformin and glyburide and optionally an insulin sensitizer such as a glitazone, for example, rosiglitazone, pioglitazone or troglitazone.
In carrying out the present invention, a low dose pharmaceutical formulation or composition will be employed containing metformin and at least one other antidiabetic agent in association with a pharmaceutical vehicle or diluent. The low dose pharmaceutical formulation can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The low dose pharmaceutical formulation of the invention can be administered to mammalian species including humans, monkeys, dogs, etc., by an oral route, for example, in the form of tablets, capsules, granules or powders, or it can be administered by a parenteral route in the form of injectable preparations. The dose for drug naive patients is as described above, which can be administered in a single dose or in the form of individual doses from 1-4 times per day.
The above dosage forms may also include the necessary physiologically acceptable carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid or sodium bisulfite) or the like.
The dose administered must be carefully adjusted according to the age, weight, and condition of the patient, as well as the route of administration, dosage form and regimen, and the desired result.
The combination of the metformin or salt thereof and the other antidiabetic agent may be formulated separately or, where possible, in a single formulation employing conventional formulation procedures.
The various formulations of the invention may optionally include one or more fillers or excipients in an amount within the range of from about 0 to about 90% by weight and preferably from about 1 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose.
One or more binders may be present in addition to or in lieu of the fillers in an amount within the range of from about 0 to about 35% and preferably from about 0.5 to about 30% by weight of the composition. Examples of such binders which are suitable for use herein include polyvinylpyrrolidone (molecular weight ranging from about 5000 to about 80,000 and preferably about 40,000), lactose, starches such as corn starch, modified corn starch, sugars, gum acacia and the like as well as a wax binder in finely powdered form (less than 500 microns) such as carnauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.
Where the composition is to be in the form of a tablet, it will include one or more tableting lubricants in an amount within the range of from about 0.2 to about 8% and preferably from about 0.5 to about 2% by weight of the composition, such as magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and the like. Other conventional ingredients which may optionally be present include preservatives, stabilizers, anti-adherents or silica flow conditioners or glidants, such as Syloid brand silicon dioxide as well as FDandC colors.
Tablets of the invention may also include a coating layer which may comprise from 0 to about 15% by weight of the tablet composition. The coating layer which is applied over the outer solid phase containing particles of inner solid phase embedded therein may comprise any conventional coating formulations and will include one or more film-formers or binders, such as a hydrophilic polymer like hydroxypropylmethylcellulose , and/or a hydrophobic polymer like methacrylic acid esters neutral polymer, ethyl cellulose, cellulose acetate, polyvinyl alcohol-maleic anhydride copolymers, xcex2-pinene polymers, glyceryl esters of wood resins and the like and one or more plasticizers, such as triethyl citrate, diethyl phthalate, propylene glycol, glycerin, butyl phthalate, castor oil and the like. Both core tablets as well as coating formulations may contain aluminum lakes to provide color.
The film formers are applied from a solvent system containing one or more solvents including water, alcohols like methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones like acetone, or ethylmethyl ketone, chlorinated hydrocarbons like methylene chloride, dichloroethane, and l,l,l-trichloroethane.
Where a color is employed, the color will be applied together with the film former, plasticizer and solvent compositions.
The finished dosage form is either a compressed tablet or a hard gelatin capsule, preferably a tablet. The tablet may be optionally film coated. The total amount of drug per dosage unit would be such as to offer a dosage form of convenient size for patients.
Where the low dose pharmaceutical formulation of the invention includes a combination of metformin and glyburide, the formulation will be administered so as to provide from about 55 to about 500 mg metformin one to four times daily, with a minimum of about 160 mg metformin daily and a maximum of less than about 800 mg, preferably up to about 750 mg metformin daily. The glyburide will preferably be administered in an amount from about 0.5 to about 3.75 mg one to four times daily, with a maximum of up to about 4.5 mg daily.
The preferred low dose pharmaceutical formulation of the invention is comprised of metformin and glyburide and is employed as initial therapy that is as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.
The ADA recommends a treatment goal of HbA1c less than 7% (ADA. Diabetes Care 21 [Suppl. 1]: S23-S31, 1998) in order to reduce the risk of complications of type 2 diabetes mellitus, including coronary heart disease and microvascular complications.
Dosage of the preferred metformin-glyburide combination of the invention must be individualized on the basis of both effectiveness and tolerance. It is preferably given with meals and should be started at a low dose, with gradual dose escalation. Ideally, the response to therapy should be evaluated using HbA1c (glycosylated hemoglobin) which is a better indicator of long-term glycemic control than FPG alone. The therapeutic goal in all patients with type 2 diabetes mellitus should be to improve glycemic control, including FPG, postprandial glucose and HbA1c levels, to normal or as near normal as possible. Patients should be titrated to achieve the ADA goal of HbA1c greater than 7% following the dosing recommendations up to the maximum recommended dose. (ADA. Diabetes Care 21 [Suppl. 1]: S23-S32, 1998).
As initial therapy, the preferred starting dose of the metformin-glyburide combination of the invention is 250/1.25 mg once a day, given with a meal. For patients with a baseline HbA1c greater than 9% or a fasting glucose  greater than 200 mg/dL, a recommended starting dose of 250/1.25 mg twice daily with the morning and evening meal may be preferred. Dosage increases should preferably be made in increments of 250/1.25 mg, every 2 weeks, up to the minimum effective dose necessary to achieve adequate glycemic control. For those patients requiring additional glycemic control, the 250 mg/1.25 mg dosage may be switched to 500/2.5 mg. However, as indicated, the preferred maximum daily dosage for metformin is 600 to 750 mg and the preferred maximum daily dosage for glyburide is 3.75 mg.
The low dose pharmaceutical formulation containing the metformin-glyburide combination, in accordance with the present invention, will preferably be formulated according to the teachings disclosed in U.S. application Ser. No. 09/353,141, filed Jul. 14, 1999, which claims priority from European application No. 98401781.4 filed Jul. 15, 1998, which U.S. application is incorporated herein by reference.
The preferred low dose metformin-glyburide formulation is set out below.
The especially preferred low dose metformin-glyburide formulations are as follows:
The low dose pharmaceutical formulation of the invention in the form of a solid oral form such as a tablet, will preferably contain a combination of metformin and glyburide in which the size of the glyburide is such that at most 10% of the particles are less than 2 xcexcm and at most 10% of the particles are greater than 60 xcexcm. Preferably, the size of the glyburide is such that at most 10 of the particles are less than 3 xcexcm and at most 10% of the particles are greater than 40 xcexcm. This specific size range of glyburide may be obtained by sieving or air jet milling.
In a second embodiment, the low dose solid oral dosage form of the invention will contain a combination of metformin and glyburide in which the size of glyburide is such that at most 25% of the particles are less than 11 xcexcm and at most 25% of the particles are greater than 46 xcexcm.
Preferably, 50% of particles are less than 23 xcexcm.
Most preferred are a combination of metformin and glyburide, where the glyburide has a particle size distribution of about 25% undersize value not more than 6 xcexcm, about 50% undersize value 7 to 10 xcexcm and about 75% undersize value not more than 23 xcexcm.
The low dose pharmaceutical formulation of the invention in the form of a tablet may be obtained by a process which includes the steps of
a) forming granules by wet granulation of a mixture of metformin and glyburide
b) blending the granules with a tabletting aid and diluent, and
c) tabletting the blend thus obtained into tablets.
The mixture used for forming the granules includes a granulating binder. The granulating binder is preferably a polyvinylpyrrolidone such as, for example, a polyvinylpyrrolidone having a molecular weight of 45,000. The polyvinylpyrrolidone may be used in a proportion of 2 to 4% by weight with respect to the final tablet.
After the granulating step, the granules may be sieved and dried.
The granules are then blended with a diluent and tableting aid. The diluent may be a conventional filler usually used for making tablets, such as microcrystalline cellulose. The tabletting aid may be a conventional material, such as magnesium stearate.
The tablets thus obtained may then optionally be coated with a hydrophilic cellulose polymer and talc. The hydrophilic cellulose polymer is preferably 2-hydroxypropyl methylcellulose.


A method of controlling write parameter selection in a memory device, can include: (i) storing a configuration set number in a configuration register, where the configuration register is accessible by a user via an interface; (ii) receiving a write command from a host via the interface; (iii) comparing the stored configuration set number against set numbers in a register block to determine a match or a mismatch; (iv) downloading configuration bits from a memory array into the register block in response to the mismatch determination; (v) selecting a configuration set corresponding to the stored configuration set number from the register block in response to the match determination; and (vi) using the selected configuration set to perform a write operation on the memory device to execute the write command.

NVM is increasingly found in applications, such as solid-state hard drives, removable digital picture cards, and so on. Flash memory is the predominant NVM technology in use today. However, flash memory has limitations, such as a relatively high power, as well as relatively slow operation speed. Other NVM technologies, such as resistive switching memory technologies that include resistive random-access memory (ReRAM) and conductive bridging RAM (CBRAM), may offer relatively lower power and higher speeds as compared to flash memory technologies. For example, CBRAM utilizes a conductive bridging cell technology, which has the potential to scale to smaller sizes than flash memory devices. In any event, write operation parameters can be utilized to set various aspects of a given write operation to the NVM device.

Write parameter switching in a memory device


A positive displacement pump, especially a high-pressure piston pump, has a piston which is mounted for reciprocation within a pumping chamber. The piston is reciprocated by a drive including a crank, a first connecting link eccentrically mounted on the crank, a second connecting link articulated to the first connecting link and to the piston, and a control link connected to said first and second connecting links for pivoting about a common axis therewith and having a free end portion supporting a roller movable along and in contact with a curved cam surface. The roller is held in contact with the cam surface by a pivotally mounted support link. A movable component of a cylinder-and-piston unit displaces the roller and thus the control link into selected positions along the cam surface in dependence on the pressure of a medium admitted thereto which corresponds to the pressure in the outlet port of the pump for adjusting the output rate of the pump to higher levels for lower pressures and to lower levels for higher pressures.

The present invention relates to pumps in general, and more particularly to high-pressure piston pumps including one or more pistons and having adjustable output rates.
It is already known to use plunger-type high-pressure pumps, in which the pressure-volume ratio remains constant, in various applications, such as in hydrodynamic cleaning operations, in hydraulic or jet mining of coal or similar substances, in operation of hydraulic presses, as process pumps in diverse treatment installations, as homogenizers, and the like. In these pumps, the output rate (the amount being pumped per unit time) remains the same as long as the speed at which the pump is driven is maintained constant. Consequently, when it is necessary to change the output rates of pumps of this type, it can be done, in one case, by providing equipment for changing the speed at which the respective pump is being driven or, in another case, in pumps of the type here under consideration where the pumping action is the result of reciprocation of at least one piston or plunger within and with respect to an associated cylinder, by providing equipment capable of adjusting the length of the stroke of the piston or plunger. The conventional equipment of this type is very complex and hence expensive.
Another possibility of adjusting the output rate of the pump of the type discussed here is to resort to the use of bypass valves in the discharge or high-pressure line of the pump or within the pump itself. As a matter of fact, because of the relative simplicity and inexpensiveness of the equipment used for achieving this expedient, this solution to the problem of adjusting the output rate of the plunger-type high-pressure pumps is currently in widespread use. Under these circumstances, an amount of the fluid being pumped which is not needed for the operation of the device to which the fluid is being supplied flows through this bypass valve back to the suction side of the pump, or more particularly into an appropriate reservoir from which the pump withdraws the fluid, and the fluid is being heated during its passage through the bypass valve and the conduits leading to the suction side. Of course, the conversion of the mechanical energy into thermal energy is disadvantageous for several reasons. First of all, the increased heat content of the fluid is usually undesirable since the consistency or other properties of the fluid may be adversely affected thereby. Thus, it is often necessary to cool the fluid before it is readmitted to the pump which, in turn, results in thermal pollution of the environment. However, even in the absence of cooling by a special cooling equipment, the increased heat content of the fluid will be dissipated into the environment, with similar consequences. Last but not least, the amount of energy which is converted into thermal energy is to be considered to be wasted in most instances, so that the overall efficiency of the pump is reduced.
When the pumps of the above type are being used for rapid approach of presses, during the pressing of protective caps against the mine roof in mining operations, during the advancement of the lining and of the mining machinery also in mining operations, it is necessary to bridge idle intervals during which the lifting cylinder-and-piston unit is to be filled. Under these circumstances, only the frictional resistance of the various parts of the equipment is to be overcome at first. In order to obtain short time intervals for these phases of the operation of the equipment, it is necessary or advantageous to supply the equipment with large amounts of the working medium during these phases of operation. Then, after the rapid-approach phase, there follows a period of time during which the pressure of the working medium which is required for operating the equipment is built up to the desired level which is then being maintained over an extended period of time.

Pump with an automatically adjusted output rate