An LED control circuit for controlling a plurality of LEDs with different emission colors comprises a counter which increments or decrements a count value at a predetermined clock in response to a count start signal externally supplied, a signal conversion circuit which converts the count value into an analog signal displaying intensity corresponding to the count value and outputs the analog signal as an output signal, a signal generation circuit which generates, based on the output signal from the signal conversion circuit and brightness data externally specified to its corresponding LED, an analog signal displaying intensity corresponding to a product of the output signal and the brightness data, and a driving circuit which drives its corresponding LED according to the analog signal output from the signal generation circuit, to gradually and simultaneously change the brightness of the LEDs in accordance with the count value.

1. Field of the Invention
The present invention relates to an LED control circuit for controlling a plurality of LEDs with different emission colors, and in particular to controlling the brightness of an LED.
2. Description of the Related Art
By using a combination of red (R), green (G), and blue (B) LEDs, i.e. three primary color LEDs, and adjusting the brightness of the LEDs, various emission colors can be produced. Such three color LEDs are incorporated in, for example, cellular and PHS mobile phones. In a cellular phone, for example, upon receipt of an incoming call or a text massage, a corresponding color light is emitted to notify a user of the receipt. As a method of realizing multicolor multi-gradation display using three color LEDs, there has been known a PWM (Pulse Width Modulation) method in which gradation of brightness of LEDs is controlled by adjusting each duty factor of pulsed voltages applied to the LEDs.
FIG. 13 shows an example of a conventional LED control circuit 100 for modulating the brightness of three color LEDs 1r, 1g, and 1b according to the PWM method. In FIG. 13, the LED control circuit 100 is connected at its input terminal to a microcomputer (micon) 200 and connected at its output terminals to the three color LEDs 1r, 1g, and 1b.
To cause the three color LEDs 1r, 1g, and 1b to enter into their respective desired lighting states, the micon 200 generates a serial data signal SDATA and supplies the serial data signal SDATA to the LED control circuit 100.
In the LED control circuit 100, a serial I/F 110 specifies various setting values in registers 121 to 127 based on the serial data signal SDATA supplied from the micon 200. Specifically, an ON-OFF setting value for turning the LEDs 1r, 1g, and 1b ON or OFF is set in the register 121, and turn-on position setting values for the LEDs 1r, 1g, and 1b are set in the registers 122, 124, and 126, respectively. Turn-off position setting values for the LEDs 1r, 1g, and 1b are set in the registers 123, 125, and 127. The turn-on position setting values define a start position of the ON period in one PWM cycle (for example, 128 of the clock count), while the turn-off position setting values define a start position of OFF period in one PWM cycle. Therefore, the duty factor of the pulsed voltage is determined by the turn-on position setting values and the turn-off position setting values.
A PWM driving circuit 141 generates a PWM signal having a desired duty factor based on the turn-on and turn-off position setting values established in the registers 122 and 123 using a clock signal for PWM generated by a counter 130. When the ON-OFF setting value for the LED 1r specified in the register 121 is "ON", the generated PWM signal is applied via an amplifier 151 to one terminal of the LED 1r, thereby causing the LED 1r to emit light at a brightness level in accordance with the duty factor of the PWM signal.
Similarly, a PWM driving circuit 142 generates a PWM signal based on the setting values in the registers 124 and 125. Then, when the ON-OFF setting value for the LED 1g specified in the register 121 is "ON", the generated PWM signal is applied via an amplifier 152 to one terminal of the LED 1g. Further, a PWM driving circuit 143 generates a PWM signal based on the setting values in the registers 126 and 127. When the ON-OFF setting value for the LED 1b specified in the register 121 is "ON", the generated PWM signal is applied via an amplifier 153 to one terminal of the LED 1b.
The LEDs 1r, 1g, and 1b are connected at their anodes to a power source Vdd and connected at their cathodes to the amplifiers 151, 152, and 153, and configured to emit light when currents are drawn into the amplifiers 151, 152, and 153.
In the LED control circuit 100 shown in FIG. 13, by individually changing the turn-on and turn-off position setting values for each of the LEDs 1r, 1g, and 1b, the LEDs 1r, 1g, and 1b can differ in brightness level from each other, which enables provision of various emission colors.
In recent years, there has been a growing demand for fade-in and fade-out functions in which the brightness level gradually increases when an LED is turned on and gradually decreases when the LED is turned off. These functions are implemented in the LED control circuit 100 shown in FIG. 13 by gradually extending the ON period for PWM to enable a fade-in, and gradually reducing the OFF period for PWM to enable a fade-out. Specifically, in a state wherein the turn-on position setting value in the register 122 is set at "0", the turn-off position setting value in the register 123 is increased from "0" to "50" by one, to thereby enable gradual increase in brightness of the LED 1r from 0/128th gradation level (turned-off state) to 50/128th gradation level.
FIG. 14 shows a fade-in and a fade-out achieved in a conventional manner. In FIG. 14, the abscissa represents time and the ordinate represents a duty factor of a PWM signal. In addition, a brightness setting value for the LED 1r (a duty factor in a normal lighting state) is set to "80/128", while the brightness setting value for the LED 1g is set to "40/128". On the other hand, the LED 1b is set to the "OFF" state.
With the above-described settings, when fade-ins, for example, of the LED 1r and the LED 1g are simultaneously started, as shown in FIG. 14, the LED 1g reaches the established brightness setting value ahead of the LED 1r, and thereafter brightness of only the LED 1r changes alone. Further, when fade-outs are simultaneously started, for example, the LED 1g reaches the turned off state (a condition where the duty factor is zero) ahead of the LED 1r, which results in a situation that only the LED 1r thereafter remains turned on.
Accordingly, in the conventional manner, when a plurality of LEDs have different brightness setting values, the brightness ratio of the plurality of LEDs could be diverted greatly from a desired brightness ratio in the course of fading in or fading out. In other words, it is not possible to perform fade-in and fade-out operation of desired halftone color light.


A hand-held pulse laser distance measuring device and a pulse reflection mixing method both having an algorithm which controls a microcontroller and which serves to calculate the distance to a measurement object by at least two different time differences τ11, τ12 between a measurement pulse and a reference pulse with a pulse width Δt, which time differences τ11, τ12 are measured with a pulse repetition frequency f1, f2, respectively, wherein a selection module is provided which selects at least the first pulse repetition frequency f1 from at least a first frequency set {f}1 with at least one other pulse repetition frequency f1i in such a way that the condition |τ11·f1i|>A >2·|Δt11·f1i| is satisfied with a pre-selected lower limit A, a relative time difference |τ1i·f1i| and a relative pulse width |Δtλ·f1i|.

1. Field of the Invention
The invention relates to a hand-held laser distance measuring device with a pulse reflection mixing method, in particular a hand-held construction laser distance measuring device.
2. Description of the Prior Art
In the building industry, distances must be exactly determined with an accuracy of within a few millimeters at a range of up to several hundreds of meters distance. The hand-held laser distance measuring devices which are suitably constructed for this purpose and to which the present invention is directed use a pulse reflection mixing method of a modulated visible laser beam for measuring distance.
In EP610918B1, a short pulse train is used for distance measurement. After detection, this short pulse train excites an electronic resonator that is adapted to the pulse train frequency. The elevated signal of the resonator causes a laser to emit a new pulse train. This process is continuously repeated so that pulse cycles occur with a determined cycle frequency. The measured distance is determined by this cycle frequency.
DE3103567C2 introduces a method for direct measurement of the light pulse time-of-flight in which a measurement light pulse traveling over the measurement distance and a reference light pulse traveling over the reference distance are detected by the same photodetector. The detected measurement light pulse and reference light pulse start and stop a time measurement system, e.g., a fast counter. The measurement distance is determined definitively by means of direct and definitive measurement of the time difference between the detection of the reference light pulse and the detection of the measurement light pulse. The maximum repetition frequency of the light pulses is accordingly limited by the condition of the definitive determination of distance.
However, it is disadvantageous that measurement is impossible when the measurement distance corresponds to one half of the reference distance because the two pulses overlap. This problem can be solved by using a switchable reference distance in the form of a light-conducting fiber so that a different reference distance can be selected in case of overlapping pulses.
DE10112833C1 discloses a hand-held laser distance measuring device with a pulse reflection mixing method. The detection pulse train detected by the light detector or, in case of separate light detectors, the reference pulse train on the one hand and the measurement pulse train on the other hand are preferably directly subjected to direct mixing in the respective light detector followed by low-pass filtering. The direct mixing is controlled by a LO pulse train which is locally generated at the measurement point and whose duty factor is equal to, or approximately equal to, the duty factor of the measurement pulse train and whose repetition frequencies are selected so as to differ slightly.
Accordingly, the mixing pulse repetition frequency fM of the low-frequency pulse train corresponds to the amount of the difference between the pulse repetition frequency f of the transmission pulse train and measurement pulse train on the one hand and the pulse repetition frequency of the local oscillator pulse train fLO on the other hand. Therefore: fM=|f−fLO|. Like the high-frequency detection pulse train, the low-frequency mixing pulse train likewise comprises reference pulses and measurement pulses whose time delay is a measure of the distance. For further particulars, the person skilled in the art is referred to the above-cited document, whose disclosure is explicitly incorporated herein in its entirety.
In hand-held laser distance measuring devices of the type mentioned above using a pulse reflection mixing method, commercially available laser diodes emitting in the visible red wavelength range are used as laser sources. The emitted laser light is modulated by a series of very narrow spike pulses, hereinafter a transmitting pulse train, and bundled into a measurement laser beam by a collimating lens. Accordingly, this special hand-held laser distance measuring device with pulse reflection mixing requires a series of very narrow laser pulses with a usual width of between 60 ps and 80 ps as a transmitting pulse train.
The pulse repetition frequency f of the laser pulses ranging from 50 MHz to 200 MHz is very high compared to the pulse repetition frequency of several tens of kHz found in conventional hand-held pulse laser distance measuring devices, so that it is generally impossible to determine distances definitively at a range of up to several hundreds of meters distance with one measurement at a determined fixed pulse repetition frequency. Therefore, at least two measurements with two substantially different pulse repetition frequencies or differences of pulse repetition frequencies f1 and f2, and for very great distance ranges with high accuracy, even n different pulse repetition frequencies, are needed for a definitive determination of distance. Using an algorithm, a microcontroller determines the time differences τk, generally in a non-definitive manner, between the reference pulses and the measurement pulses of the low-frequency mixing pulses at different pulse repetition frequencies fk and, from the latter, determines the distance from the rangefinder to the light spot on the measurement object by means of the light velocity.
At certain distances with a time difference τk=0, an overlapping of the reference pulse and measurement pulse results due to a finite pulse width Δt. Since this renders measurement impossible, the microcontroller in this case chooses a slightly different pulse repetition frequency fki at which no overlapping occurs. It is disadvantageous that an increased distance measurement error must be taken into account even with a small τk because the two pulses influence one another due to the small distance.
In the following, the time difference between a reference pulse and a measurement pulse with respect to the period λ=1/fk is referred to as the relative time difference τk·fk and the pulse width with respect to the period λ=1/fk is referred to as the relative pulse width Δtλ·fk.
The object of the invention is to realize a hand-held laser distance measuring device with pulse reflection mixing having increased distance measuring accuracy. A further object is an algorithm for generating pulse repetition frequencies that are optimal with respect to distance measuring accuracy.

Hand-held laser distance measuring device with a pulse reflection mixing method


The water-treatment processes of this invention utilize maleate copolymers to sequester water hardness ions, modify crystal formation in water and inhibit scale formation (e.g., in circulating water systems and oil field production systems), which polymers contain from about 40 to 70 mole percent of dicarboxylic functionality provided by a maleate monomer upon polymerization, from about 1 to about 15 mole percent of the polymerized residue of a non-ionic monomer, and from about 20 to about 50 mole percent of monocarboxylic functionality.

It is known that maleic acid in aqueous solutions does not readily form homopolymers, but will quite rapidly copolymerize with various other ethylenically unsaturated monomers, typically to form 1:1 molar ratio maleate:comonomer copolymers.
In most cases, maleate copolymers are prepared by a solution polymerization process employing organic solvents. For example, U.S. Pat. No. 4,710,537, issued Dec. 1, 1987 to Walinsky, teaches the preparation of a substantially homogeneous copolymer, consisting essentially of 35 to 65 mole percent acrylate and 65 to 35 mole percent maleate units and having a number average molecular weight of about 500 to 5,000. The copolymer is prepared in a chain-transfer solvent, preferably a ketone, ester, or ether having from 4 to 10 carbon atoms. Following polymerization, an aqueous solution of the copolymer may be prepared by adding water to the polymerization flask and distilling off the organic solvent.
For reasons of safety, efficiency in manufacturing and waste handling, it is desirable to polymerize the maleate copolymers in aqueous solution, rather than in organic solvent. An aqueous solution preparation of maleate copolymers is disclosed in Japanese Patent Application JP 60-212,410, published Oct. 24, 1985 by Fukumoto, et al. The polymerization method provides maleate copolymers with mean molecular weights of 300 to 5,000 and has a reported "polymerization rate" of, at most, 96.2%. The "polymerization rate" is the difference between the weight of monomer initially charged and the weight of copolymer recovered following polymerization (i.e., a measure of the unreacted residual monomer).
Another method for preparation of maleate copolymers in aqueous solution is disclosed in U.S. Pat. No. 4,519,920, issued May 28, 1985, to Fukumoto, et al. This process provides an initial, partial neutralization of the maleate monomer with alkali. A similar aqueous solution process for producing a polymaleate, with an option to copolymerize up to 20 mole percent of an unsaturated carboxylic acid comonomer, is disclosed in U.S. Pat. No. 4,668,735, issued May 26, 1987, to Fukumoto, et al.
U.S. Pat. No. 3,635,915, issued Jan. 18, 1972 to Gale discloses a process for preparing maleate/acrylate copolymers in aqueous solution using an inorganic peracid salt as a catalyst. The copolymers are prepared from 50 to 95 parts of acrylic acid and 5 to 50 parts of maleic acid, on a monomer weight basis (i.e., 57.5 to 96.5 mole percent acrylate and 3.5 to 42.5 mole percent maleate).
U.S. Pat. No. 4,659,793, issued Apr. 21, 1987, to Yang claims an aqueous polymerization process for manufacturing copolymer having a low residual free monomer content from carboxylic acid monomers and various comonomers. In the claimed process a metallic ion redox catalyst is used to prepare a copolymer comprising 25 to 55 weight percent (i.e., 21 to 47 mole percent) dicarboxylic acid monomer.
U.S. Pat. No. 4,314,044, issued Feb. 2, 1982 to Hughes, et al., claims an aqueous polymerization process for manufacturing copolymers of carboxylic acid monomers using a metallic ion redox catalyst system. As exemplified in the patent, the process only achieves about 95% monomer conversion. About 5 to 50 weight percent dicarboxylic acid is polymerized in the claimed process.
We have now discovered that an aqueous solution polymerization, employing a combination of at least 50 mole percent, preferably at least 70 mole percent charge preneutralization of the maleate monomer, a redox initiator catalyst using metallic ion, a slow feed addition of at least one comonomer, preferably over a period of at least three hours, to the neutralized maleate monomer and a post-feed of a polymerization initiator provides a copolymer having a weight average molecular weight of about 1,000 to 4,000, comprising less than 1%, on a copolymer weight basis, of residual, free monomer. This process may be carried out under ambient atmospheric conditions. An inert atmosphere, such as nitrogen, is not required for the polymerization. The resulting copolymer is useful as an antiscalent, an anti-incrustation agent, a dispersant, a sequestrant and a water hardness salt (e.g., calcium carbonate, magnesium carbonate, magnesium sulfate, magnesium hydroxide, calcium sulfate, calcium silicate, magnesium silicate and barium sulfate) crystal modifier. The maleate copolymers of this invention are preferably prepared by an aqueous solution polymerization process and may be used to sequester water hardness ions, modify crystal formation in water and inhibit scale formation (e.g., in circulating water systems and oil field production systems). The maleate copolymer comprises from about 40 to 70 mole percent of dicarboxylic functionality provided by a maleate monomer upon polymerization, for instance maleic acid, from about 1 to about 15 mole percent of the polymerized residue of a non-ionic monomer, e.g. acrylamide or vinyl acetate, and from about 20 to about 50 mole percent of monocarboxylic functionality, provided either by a carboxylic acid, containing at least one activated carbon-to-carbon olefinic double bond and at least one carboxyl group, upon polymerization with the maleate monomer and the non-ionic monomer, or generated in-situ by hydrolysis of one of the non-ionic monomers which is hydrolyzable under acidic or basic pH conditions, for example acrylamide.

National Starch and Chemical Investment Holding Corporation


A mechanically expandable esophageal medical lead has an elongated flexible body which carries at a distal end thereof one or more electrically conducting members. The conducting members are moveable laterally with respect to the body portion of the medical lead by means of a mechanical structure contained therein. The degree and extent of mechanical movement can be controlled through manipulation of a pull wire axial movement mechanism.

U.S. Pat. No. 4,817,611 to Arzbaecher et al. entitled "Esophageal Electrocardiography Electrodes" discloses a bipolar electrode usable for esophageal cardiac pacing or cardiac monitoring. The bipolar electrode of the Arzbaecher et al. patent has a molded plastic body which lockingly carries first and second spaced-apart conducting bands.
Other types of esophageal insertable devices are known in the art. Some of these have regions or balloons which may be inflated to block portions of the esophagus or for positioning a unit in the esophagus. Those devices typically require the introduction of air, saline or other fluid for inflation and distention.
Few known devices provide a simple mechanically expandable electrode carrying member which, as a result of expansion and distention, provide improved contact between the interior surface of the esophagus and the conducting elements of the electrode and that also may be reoriented within the esophagus after emplacement to position the stimulating or monitoring electrodes disposed on the distal end thereof in closer proximity to cardiac tissue. Thus, there continues to exist a need for esophageal medical leads that may be easily expanded upon insertion and subsequently repositioned, but that are also cost effective to manufacture.
Disclosures relating to transesophageal and other devices include the patents and other references listed below in Table 1.
TABLE 1 ______________________________________ Prior Art Publications ______________________________________ U.S. Patents 3,517,128 6/1970 Hines 606/198 4,304,240 12/1981 Perlin 128/642 4,576,162 3/1986 McCorkle 128/419P 4,640,298 2/1987 Pless et al 128/784 4,699,147 10/1987 Chilson et al. 128/642 4,706,688 11/1987 Don Michael et al. 128/785 4,722,347 2/1988 Abrams et al. 128/663 4,817,611 4/1989 Arzbaecher et al. 128/642 4,883,070 11/1989 Hanson 128/419P 4,920,979 5/1990 Bullara 128/784 4,930,521 6/1990 Metzger et al. 128/786 4,946,457 8/1990 Elliott et al. 606/1 5,010,894 4/1991 Edhag et al. 128/785 5,117,828 6/1992 Metzger et al. 128/642 5,154,387 10/1993 Trailer 128/784 5,170,803 12/1992 Hewson et al. 128/786 5,263,493 11/1993 Avitall 7/1992 5,370,679 12/1994 Atlee, III 607/124 5,379,765 1/1995 Kajiwara et al. 128/642 5,406,946 4/1995 Imran 128/642 5,417,713 2/1993 Cohen 607/4 5,431,696 7/1995 Atlee, III 607/124 5,449,381 9/1995 Imran 607/122 Foreign Patents 0009732 4/1980 European Patent Org. 128/786 Technical Papers "Trans-Esopageal Pacing," Andersen et al., PACE, Vol. 6, pp. 674-679, July, 1983. "Atrial Pacing Thresholds Measured in Anesthetized Patients with the Use of an Esophageal Stethoscope Modified for Pacing," Pattison et al., Anesthesiology, Vol. 74, pp. 854-858, May, 1991. "Transesophageal Atrial Pacing -- Stimulation and Discomfort Thresholds: The Role of Electrode Configuration and Pulse Width," Res et al., PACE, Vol. 14, pp. 1359-1366, September, 1991. "Esophageal Balloon Electrode Catheter for Transthoracic Recording of His-Bundle Potential with Transesophageal Atrial Pacing," Heinke et al., PACE, vol. 17, pp. 2125-2128, November, ______________________________________ 1994.
As those skilled in the art will appreciate upon reading the Summary of the Invention, Detailed Description of the Preferred Embodiments and Claims set forth below, at least some of the devices and methods disclosed in the patents of Table 1 may be modified advantageously by using the teachings of the present invention.


A method of erasing a chalcogenide variable resistance memory cell is provided. The chalcogenide variable resistance memory cell includes a p-doped substrate with an n-well and a chalcogenide variable resistance memory element. The method includes the step of applying to the variable resistance memory element a voltage that is less than a fixed voltage of the substrate. The applied voltage induces an erase current to flow from the p-doped substrate through the n-well and through the variable resistance memory element.

Microprocessor-accessible memory devices have traditionally been classified as either non-volatile or volatile memory devices. Non-volatile memory devices are capable of retaining stored information even when power to the memory device is turned off. However, non-volatile memory devices occupy a large amount of space and consume large quantities of power, making these devices unsuitable for use in portable devices or as substitutes for frequently-accessed volatile memory devices. On the other hand, volatile memory devices tend to provide greater storage capability and programming options than non-volatile memory devices. Volatile memory devices also generally consume less power than non-volatile devices. However, volatile memory devices require a continuous power supply in order to retain stored memory content.
Commercially viable memory devices that are both randomly accessed and semi-volatile or non-volatile are desired. Various implementations of such semi-volatile and nonvolatile random access memory devices are being developed. These devices store data in a plurality of memory cells by structurally or chemically changing the resistance across the memory cells in response to predetermined voltages applied to the memory cells. Examples of variable resistance memory devices being investigated include memories using variable resistance polymers, perovskite, doped amorphous silicon, phase-changing glasses, or doped chalcogenide glass, among others.
In a variable resistance memory cell, a first value may be written to the variable resistance memory cell by applying a voltage having a predetermined level. The applied voltage changes the electrical resistance across the memory cell. A second value, or the default value, may be written or restored in the memory cell by applying a second voltage to the memory cell, thereby changing the resistance across the memory cell to the original resistance level. The second voltage is typically a negative voltage in comparison to the first voltage and may or may not have the same magnitude as the first voltage. Each resistance state is stable, so that the memory cells are capable of retaining their stored values without being frequently refreshed. The variable resistance materials can thus be "programmed" to any of the stable resistance values.
The content of a variable resistance memory cell is read or "accessed" by applying a read voltage to determine the resistance level across the cell. The magnitude of the read voltage is lower than the magnitude of the voltage required to change the resistance of the variable resistance memory cell. In a binary variable resistance memory cell, upon determining the resistance level of the variable resistance memory cell, the detected resistance level is compared with a reference resistance level. Generally, if the detected resistance level is greater than the reference level, the memory cell is determined to be in the "off" state. On the other hand, if the detected resistance level is less than the reference level, the memory cell is determined to be in the "on" state.
FIG. 1 shows a basic composition of a variable resistance memory cell 10 constructed over a substrate 12, having a variable resistance material 16 formed between two electrodes 14, 18. One type of variable resistance material may be amorphous silicon doped with V, Co, Ni, Pd, Fe and Mn as disclosed in U.S. Pat. No. 5,541,869 to Rose et al. Another type of variable resistance material may include perovskite materials such as Pr(1−x)CaxMnO3 (PCMO), La(1−x)CaxMnO3 (LCMO), LaSrMnO3 (LSMO), GdBaCoxOy (GBCO) as disclosed in U.S. Pat. No. 6,473,332 to Ignatiev et al. Still another type of variable resistance material may be a doped chalcogenide glass of the formula AxBy, where "B" is selected from among S, Se and Te and mixtures thereof, and where "A" includes at least one element from Group IIIA (B, Al, Ga, In, Tl), Group IVA (C, Si, Ge, Sn, Pb), Group VA (N, P, As, Sb, Bi), or Group VIIA (F, Cl, Br, I, At) of the periodic table, and with the dopant being selected from among the noble metals and transition metals, including Ag, Au, Pt, Cu, Cd, Ir, Ru, Co, Cr, Mn or Ni, as disclosed in U.S. Published Application Nos. 2003/0045054 and 2003/0047765 to Campbell et al. and Campbell, respectively. Yet another type of variable resistance material includes a carbon-polymer film comprising carbon black particulates or graphite, for example, mixed into a plastic polymer, such as that disclosed in U.S. Pat. No. 6,072,716 to Jacobson et al. The material used to form the electrodes 14, 18 can be selected from a variety of conductive materials, such as tungsten, nickel, tantalum, titanium, titanium nitride, aluminum, platinum, or silver, among others.
In FIG. 2, a typical prior art variable resistance memory cell 100 is shown to include an access device 102, a variable resistance memory element 104, and a cell plate 110. The access device 102 is a transistor having a gate 102a coupled to a word line 106 and one terminal (source) 102b coupled to a bit line 108. The other terminal (drain) 102c of the access device 102 is coupled to one end of the variable resistance memory element 104, while the other end of the variable resistance memory element 104 is coupled to the cell plate 110. The cell plate 110 may span and be coupled to several other variable resistance memory cells, and may form the anode of all the memory elements 104 in an array of variable resistance memory cells. The cell plate 110 is also coupled to a potential source 112.
A representative diagram of the physical structure of the prior art memory cell 100 is shown in FIG. 3. In particular, a p-doped substrate 126 includes two n-wells 120, 122. Access device 102 is formed on the surface of the substrate 126 between the two n-wells 120, 122, so that the two n-wells 120, 122 serve as the source 102b and drain 102c, respectively, of the access device 102. Word line 106 is formed as a conductive strip extending into the page across the top of access device 102. Bit line 108 is connected directly to the n-well 120 forming the source 102b of the access device 102. Variable resistance memory element 104 is formed on the substrate with its cathode 114 in contact with n-well 122 and the cell plate 110 (only a portion of which is shown) as its anode. The cell plate 110 of memory element 104 is connected to a potential source 112.
In the conventional operating scheme for the cell 100, when the memory element 104 is idle, the voltage across the anode 110 and the cathode 114 is below a threshold voltage VG. The value of the threshold voltage VG is a function of the specific variable resistance material used in the memory element 104. In order to perform any access operations including programming the variable resistance memory element 104 to the low resistance state, erasing a programmed variable resistance memory element 104 by returning the variable resistance memory element 104 to the high resistance state, or reading the value stored in memory element 104, the threshold voltage VG must be applied to the word line 106. The voltage VG on the word line 106 activates the gate 102a of the access device 102 so that an n-channel is formed in the substrate 126 under the gate structure of the access device 102 and across the gap between the two n-wells 120, 122 thus activating the access device 102 . Upon activating the access device 102, the memory element 104 can be programmed to the low resistance state by applying a write (positive) voltage having at least the magnitude of a threshold voltage VTW across the memory element 104.
In conventional operating schemes, application of the write voltage may be achieved by raising the potential at the cell plate 110 (anode) relative to the access device drain 102b by applying or raising the voltage at the potential source 112, lowering the potential of the bit line 108, or a combination of both. To erase a programmed memory element 104, a negative voltage having a magnitude of at least a threshold erase voltage is applied between the anode and the cathode of the memory element 104, such that the potential at the cell plate 110 is lower than the potential of the bit line 108.
Variable resistance memory cells are arranged as an array of memory cells and are written, erased, and read using a controller. FIG. 4 illustrates a prior art memory device 200 comprising an array of memory cells 100a–100f arranged in rows and columns. The memory cells 100a–100f along any given bit line 108a, 108b do not share a common word line 106a–106c. Conversely, the memory cells 100a–100f along any given word line 106a–106c do not share a common bit line 108a–108b. In this manner, each memory cell is uniquely identified by the combined selection of the word line to which the gate of the memory cell access device is connected, and the bit line to which the source of the memory cell access device is connected.
Each word line 106a–106c is connected to a word line driver 202a–202c via a respective transistor 204a–204c for selecting the respective word line for an access operation. The gates of the transistors 204a–204c are used to selectively couple or decouple the word lines 106a–106c to or from the word line drivers 202a–202c. Similarly, each bit line 108a, 108b is coupled to a driver 206a, 206b via selector gates 208a, 208b. The current and/or resistance of a selected memory cell 100a–100f is measured by sensor amplifiers 210a, 210b connected respectively to the bit lines 108a, 108b.
For simplicity, FIG. 4 illustrates a memory array having only two rows of memory cells 100 on two bit lines 108a–108b and three columns of memory cells 100 on three word lines 106a–106c. However, it should be understood that in practical applications, memory devices would have significantly more cells in an array. For example, an actual memory device may include several million memory cells 100 arranged in a number of subarrays.
While the overall operating scheme of the memory device 200 may be similar regardless of the type of variable resistance material used in the memory elements, much research has focused on memory devices using memory elements having doped chalcogenide materials as the variable resistance material. More specifically, memory cells having a variable resistance material formed of germanium-selenide glass having a stoichiometry of GexSe(100−x), with x ranging from about 20 to about 43, which are doped with metal ions, have been shown to be particularly promising for providing a viable commercial alternative to traditional random-access memory devices.
Generally, a metal ion doped chalcogenide variable resistance memory cell having such stoichiometry has an initial "off" state resistance of over 100 k (for example, 1 M ). To perform a write operation on a chalcogenide memory cell in its normal high resistive state, a voltage having at least a threshold potential is applied to the electrode serving as the anode, with the cathode held at the reference potential or ground. Upon applying the threshold level or write voltage, the resistance across the memory cell changes to a level dramatically reduced from the resistance in its normal state. The new resistance of the memory cell is less than 100 k (for example, 20 k ). The cell is considered to be in the "on" state while in the low-resistive state.
The variable resistance memory cell retains this new lower level of resistivity until the resistivity is changed by another qualifying voltage level applied to one of the electrodes of the cell. For example, the memory cell is returned to the high resistance state by applying an erase voltage thereto in the negative direction of the voltage applied in the write operation (to achieve the lower resistance state). The erase voltage may or may not be the same magnitude as the write voltage, but is at least of the same order of magnitude.
Such chalcogenide variable resistance memory cells can retain a low-resistance state for several hours, days, or even weeks and are relatively non-volatile compared with typical random-access memory devices. However, while metal ion doped chalcogenide variable resistance memory cells in the high resistance state are completely non-volatile, variable resistance memory cells written to the low resistive state may gradually lose their conductivity across the chalcogenide glass layer and drift towards the high resistive state after an extended period of time. In particular, it has been found that metal ion doped chalcogenide variable resistance memory devices which are written using write voltages with pulse widths of less than 100 ns have a tendency to gradually lose their low resistance characteristic in as little as a week. Accordingly, such variable resistance memory devices may require some intermittent refreshing to maintain optimal operation of the devices.
In addition to intermittent refresh operations, metal ion doped chalcogenide variable resistance memory cells may require an occasional reset operation to reset the bistable resistance levels. Over time, the resistance levels resulting from application of various threshold voltages tend to drift. The driffing voltage/resistance (V/R) relationship is further explained below in the context of write and erase operations via measured voltage/resistance curves.
A standard voltage/resistance curve for a write operation performed on a properly functioning metal ion doped chalcogenide variable resistance memory cell is illustrated in FIG. 6A. A voltage/resistance curve, such as that shown in FIG. 6A, is derived by measuring the resistance across the chalcogenide variable resistance memory cell as a function of voltage for a given current. The initial or normal resistance level of a chalcogenide variable resistance memory cell is shown as ROFF, which is above a minimum threshold level REMin in which the chalcogenide variable resistance memory cell is stable in a high resistance state. When the chalcogenide variable resistance memory cell is in the high resistance state and VTW is applied to the cell, the resistance drops to the level indicated by RON, which is below a maximum threshold level RWMax in which the chalcogenide variable resistance memory cell is stable in a low resistance state.
FIG. 5B shows the same programming circuit 300 illustrated in FIG. 5A, except that an erase voltage VTE is applied to the bottom electrode 114 to illustrate an erase operation. By way of example, VTE has a voltage level of −0.75 V and a pulse width of about 8 ns. Upon the application of VTE to the bottom electrode 114 of the chalcogenide variable resistance memory cell 310, the chalcogenide variable resistance memory cell 310 returns to its high resistance ("off") state, thus erasing the binary value of "1" previously written in the cell, so that the value of "0" is again stored in the chalcogenide variable resistance memory cell 310.
FIG. 6B shows a typical voltage-resistance curve for a metal ion doped chalcogenide variable resistance memory cell during an erase operation. As in FIG. 6A, RON indicates the resistance level of the memory cell in the low resistance ("on") state, and RWMax represents the maximum resistance value at which the memory cell is stable in the low resistance state, while ROFF indicates a resistance level of the memory cell in the high resistance ("off") state, and REMin demonstrates the minimum resistance value at which the memory cell is stable in the high resistance state. When the metal ion doped chalcogenide variable resistance memory cell is in the low resistance state and VTE is subsequently applied to the cell, the resistance in the chalcogenide variable resistance memory cell increases to the level indicated by ROFF. It is noted that the write voltage VTW is not necessarily of the same magnitude as the erase voltage VTE.
However, as mentioned above, the resistance profiles of metal ion doped chalcogenide variable resistance memory cells have a tendency to shift after a number of read or write operations have been applied to the cell. Specifically, the cell may eventually be written into an "on" state in which the resistance in that state is unacceptably high or unacceptably low, or an erase operation may place the cell in an "off" state in which the resistance in that state is unacceptably low or unacceptably high. This can happen in as few as about 400 write and erase cycles. Typical life expectancies for random access memory devices are on the order of 1014 write/erase cycles. Thus, the resistance drift should be corrected for longevity of operation of the memory cell.
The phenomenon of resistance drift is demonstrated in FIG. 7, which depicts the case when the chalcogenide variable resistance memory cell drifts towards a low resistance "off" state RDE, meaning that after repeated cycles over time, the "off" state resistance achieved upon application of the fixed erase voltage VTE falls below the level ROFF shown in FIG. 6B. Similarly, the memory cell exhibits an unusually low resistance "on" state RON. The resistance RON becomes progressively more variable and drifts increasingly lower upon the performance of repeated erase cycles until application of the threshold erase voltage VTE is consistently insufficient to bring the memory cell to the minimum stable high resistance level REMin, as illustrated in FIG. 6. Once this condition is reached, subsequent erase operations will fail to erase the stored value in the chalcogenide variable resistance memory cell, causing a breakdown in the ftmction of the chalcogenide variable resistance memory device. Additionally, continued write cycles applied to these already low resistance state memory cells result in pushing the memory cells into an even lower resistance state.
A solution to the voltage/resistance curve shift problem described above and illustrated in FIG. 7 is to periodically reset the memory cells to an original high resistance level. An applied reset or "hard" erase pulse serves to reestablish the original resistance profile of the memory cell in the high resistance state. The "hard" erase pulse may be applied by increasing the voltage level and/or the pulse width relative to erase voltage VTE applied in a normal erase operation. A "normal" erase pulse is illustrated in FIG. 8A having, for example, a voltage level of −0.8 V and a duration of 8 ns. A first type of "hard" erase pulse is shown in FIG. 8B, in which the applied pulse is the same duration as the normal erase pulse, but has a negative voltage level of a magnitude greater than the −0.8 V of the normal erase pulse. An alternative "hard" erase pulse is shown in FIG. 8C, in which the "hard" erase pulse has the same magnitude as the normal erase pulse, but has a longer pulse width. In a further alternative, the "hard" erase pulse may have both a greater magnitude and a longer duration than the normal erase pulse. The amount by which the voltage level or the duration of the "hard" erase pulse exceeds that of the normal erase pulse may vary depending on the amount of drift, or the amount by which RDE falls below REMin.
A significant challenge exists in determining an appropriate magnitude of an applied "hard" erase voltage pulse, as illustrated in FIGS. 9A, 9B and 9C. A proposed metal ion doped chalcogenide variable resistance memory cell 500 is depicted in FIG. 9B, comprising a p-doped substrate 526 and two n-wells 520, 522. An access device 502 is depicted as a transistor, and is shown in both FIGS. 9A and 9B. The access device 502 is activated by an "on" word line 506 (i.e., a word line having a voltage sufficient to activate access device 502), which is connected to the gate of the transistor. The active access device 502 allows current to flow between the bit line 508 (connected to the source of the transistor) and the cell plate 510 (connected through the variable resistance memory element 504 to the drain of the transistor). In other words, when the access device 502 is activated, current must flow through two series resistances (refer to FIG. 9C). One resistance, the cell resistance, Rcell, is highly variable, due to the drifting RON and RDE levels, as described in detail above. Typically, Rcell can range anywhere from 5 k● to 46 k●. The other resistance that must be accounted for is the channel resistance, Rchannel, which is generally about 30 k●. With both resistances Rcell, Rchannel in series, a voltage divider equation must be solved in order to determine the voltage across the chalcogenide variable resistance memory cell 504.
                              V          cell                =                                            (                                                V                  BL                                -                                  V                  cpin                                            )                        *                          R              cell                                                          R              cell                        +                          R              channel                                                          Eq        .                                          1            Using Equation 1, and setting (for purposes of example only) VBL to equal 2.2 V and Vcpin to equal 0.6 V, the value of Vcell will range from 0.23 V to 0.97 V as a result of the variable resistance of Rcell. In other words, if the resistance-voltage curve for the chalcogenide variable resistance memory cell has drifted too low, as shown in FIG. 7, then a normal "hard" erase voltage applied to VBL and Vcpin may not create a sufficient differential to actually reset the chalcogenide variable resistance memory cell.
From the discussion above, it should be appreciated that an improved method for effectuating a "hard" erase of a chalcogenide variable resistance memory cell is both needed and desired.

Process for erasing chalcogenide variable resistance memory bits


A driving assist system for vehicle calculates risk potential from the traveling environment of vehicle surroundings, and calculates a reference speed Vt while the vehicle is traveling. Accelerator pedal reaction force control amount is then calculated based on the risk potential RP and the reference speed Vt. The accelerator pedal reaction force is controlled so as to generate the calculated reaction force control amount, and information relating to the risk potential RP and the reference speed Vt is conveyed to the driver through sense of touch.

1. Field of the Invention
The present invention relates to a drive operation assist device for a vehicle, for assisting operations carried out by a driver.
2. Description of Related Art
Systems that assist driver operations include the system disclosed in Japanese Patent Laid-open Publication No. H10-166889. This system changes operation reaction force of an accelerator pedal based on inter-vehicle distance between a preceding vehicle and a subject vehicle. Warning is given to a driver by increasing reaction force of the acceleration pedal as the distance between vehicles decreases. Japanese Patent Laid-open Publication No. H10-166890 and 2000-54860 also disclose systems that assist driver operations.


A voltage equalizer for battery elements for equalizing terminal voltages of a plurality of battery elements comprises an equalization processing circuit. The equalization processing circuit includes a transformer having basic windings. The basic windings comprise a plurality of primary windings corresponding to the plurality of battery elements and one or more secondary windings, a plurality of switching elements corresponding to the battery elements, a plurality of primary diodes corresponding to the battery elements, and one or more secondary diodes corresponding to the secondary windings. In the voltage equalizer, primary series circuits for carrying current from the battery elements via the corresponding primary diodes to the primary windings and secondary series circuits for carrying current from the secondary windings via the secondary diodes to the battery elements are formed.

The present invention relates to a voltage equalizer for battery elements for equalizing terminal voltages of battery elements which constitute a battery or the like.
In general, a battery including a number of (for example, about one hundred) battery elements which are connected in series to each other is installed in an electric vehicle which is run by a motor or a hybrid vehicle which is run in combination of an engine and a motor. Then, a voltage equalizer is connected to the battery in consideration of securement of a charging capacity, extension of the life of each battery element and safety. Further, a voltage detector for detecting an abnormal terminal voltage of each battery element is also connected to the battery to eliminate a risk of the occurrence of a serious secondary failure which would be caused by heat and leakage of fluid which are caused in the event that there occurs a short circuit in one of the battery elements.
Conventionally, as a voltage equalizer of this type, a voltage equalizer for battery elements is known which was proposed by the applicant of the present invention and is disclosed in JP-A-2002-223528. In this voltage equalizer, a closed circuit is configured by battery elements of one of a plurality of groups of battery elements which are connected in series, each of a plurality of secondary windings which are magnetically connected to each other and each of one of pluralities of switching elements, and a closed circuit is configured by battery elements of the other group of battery elements, primary windings which are magnetically connected to the secondary windings in a common fashion and the other plurality of switching elements, whereby the output voltage of the one of a plurality of groups of battery elements which are connected in series is equalized by ON/OFF controlling the one of pluralities of switching elements and the other plurality of switching elements alternately.
In addition, as the voltage detector, a voltage detection circuit for battery elements is known which has already been proposed by the applicant of the present invention and is disclosed in JP-2002-357625. This voltage detection circuit is a voltage detection circuit for battery elements for detecting a voltage between terminals of each of a plurality of battery elements which are connected in series to each other which has a voltage detection means connected between terminals of each of the plurality of battery elements and adapted to cause a detection current to flow from an output terminal when a predetermined voltage is reached and a single detection signal output means connected via a load resistance to a negative terminal of a battery element, which is positioned on a minimum potential side, of the plurality of battery elements which are connected in series to the output terminal of the voltage detecting means, whereby a sufficient current for the single detection signal output means to output a detection signal can securely be allowed to flow even in the event that any of the battery elements reaches a predetermined voltage which is set in advance.
In the afore said conventional voltage equalizer (and the voltage detector), however, there exist the following problems to be solved.
As a first problem, when paying attention to the voltage equalizer, since energy is temporarily stored in the transformer and thereafter, a substantial equalization process is carried out, there still remains a room for improvement from equalization capability and equalization efficiency (equalization time) perspectives. In addition, since an equalization process is performed between all of the battery elements, respectively, there exists a risk that excessive charging and discharging currents are generated in case terminal voltages between the battery elements vary largely.
As a second problem, in a case where the voltage detector is connected in addition to the voltage equalizer, since they constitute two dedicated devices which are independent from each other, a configuration is generated in which the two dedicated devices are combined with the battery elements, and this calls for increase in cost, enhancement of energy loss and enlargement of size of the entire system.
As a third problem, when paying attention to the voltage detector, since the terminal voltage of each battery element is detected through an independent detection circuit, a number of detection circuits which corresponds to the number of battery elements are required, and in case the number of battery elements is increased, this calls for an increase in components cost in conjunction with a remarkable increase in the number of components and an increase in production costs in association with the complexity of circuits. In addition, the size of the system is also increased, and this constitutes a cause for the prevention of the effort to save space in an electric vehicle where components layout space is limited, and wasteful energy loss is also increased.


A power switch includes an operating button, an elastic member, a printed circuit board, a support member, and a fixing module. The operating button includes a connecting portion. The elastic member includes a fixing portion and an elastic portion. The printed circuit board includes a main body and a contacting element. The support member includes a base portion and a receiving portion perpendicularly extending from the base portion, and the base portion defines a hole communicating with the receiving portion. The fixing module includes a cover and a contacting member formed on the cover. The connecting portion of the operating button is fixed to the main body and is received in the hole of the support member and the receiving portion. The fixing portion of the elastic member is sandwiched between the connecting portion of the operating button and the main body.

1. Technical Field
This disclosure generally relates to electronic devices, and particularly, to an electronic device with a power switch.
2. Description of Related Art
Many electronic devices have a power switch for turning the electronic device on/off. Such electronic devices include a housing defining a receiving hole, and the power switch is received in the receiving hole. The power switch includes an operating button, a support member, a printed circuit board, and an elastic piece which is installed between the operating button and the printed circuit board. When the operating button is pressed to contact the electrical contacts of the printed circuit board, the electronic device turns on. When assembling the power switch in the housing, the operating button is inserted into the receiving hole, and the elastic piece is fixed to a surface of the operating button adjacent to the printed circuit board, and the support member is fixed to the housing, such that the elastic piece is located between the operating button and the printed circuit board and a space is reserved for allowing deformation of the elastic piece. However, in the assembly process, a technician must manually align the operating button with the elastic piece, which is time consuming and often produces imprecise results.
Therefore, there is room for improvement in the art.

Fu Tai Hua Industry (Shenzhen) Co., Ltd.


Apparatus, systems, and methods may operate to grant a renewable lease synchronization lock to a node for a file having copies distributed among a group of nodes that is unsynchronized and for which no write lock has already been granted. The synchronization lock disables modification of the file, and enables synchronization of a file copy on the requesting node to a synchronization master copy on another node in the group. A renewable lease write lock can be granted to a node in the group when the file is synchronized and when the write lock has not already been granted. The write lock disables granting the synchronization lock, and enables file modification. The synchronization lock and write lock are maintained until their respective leases expire. Additional apparatus, systems, and methods are disclosed.

In a distributed data processing environment, multiple copies of the same file may be kept on multiple nodes to provide faster access and data redundancy. A replication protocol based on modification time stamps can operate to maintain integrity between the copies, eventually updating unmodified copies of the file to include changes as they are made. However, this means that later modifications receive update precedence over earlier modifications, when each occurs after the last synchronization event. Thus, some (earlier) modifications can be ignored, resulting in permanent data loss.


Examples of systems are described herein which may dynamically allocate compute resources to recovery clusters. Accordingly, a recovery site may utilize fewer compute resources in maintaining recovery clusters for multiple associate clusters, while ensuring that, during use, compute resources are allocated to a particular cluster. This may reduce and/or avoid vulnerabilities arising from a use of shared resources in a virtualized and/or cloud environment.

A virtual machine (VM) generally refers to a software-based implementation of a machine in a virtualization environment, in which the hardware resources of a physical computer (e.g., CPU, memory, etc.) are virtualized or transformed into the underlying support for the fully functional virtual machine that can run its own operating system and applications on the underlying physical resources just like a real computer.
Virtualization generally works by inserting a thin layer of software directly on the computer hardware or on a host operating system. This layer of software contains a virtual machine monitor or "hypervisor" that allocates hardware resources dynamically and transparently. Multiple operating systems may run concurrently on a single physical computer and share hardware resources with each other. By encapsulating an entire machine, including CPU, memory, operating system, and network devices, a virtual machine may be completely compatible with most standard operating systems, applications, and device drivers. Most modern implementations allow several operating systems and applications to safely run at the same time on a single computer, with each having access to the resources it needs when it needs them.
One reason for the broad adoption of virtualization in modern business and computing environments is because of the resource utilization advantages provided by virtual machines. Without virtualization, if a physical machine is limited to a single dedicated operating system, then during periods of inactivity by the dedicated operating system the physical machine may not be utilized to perform useful work. This may be wasteful and inefficient if there are users on other physical machines which are currently waiting for computing resources. Virtualization allows multiple VMs to share the underlying physical resources so that during periods of inactivity by one VM, other VMs can take advantage of the resource availability to process workloads. This can produce great efficiencies for the utilization of physical devices, and can result in reduced redundancies and better resource cost management.
In public cloud environments, resources are usually shared between tenants. Amazon AWS, Microsoft's Azure and Google's GCP are examples of this design. The resources may employ common physical hardware (e.g., Intel CPUs). Vulnerabilities may be found in such hardware (e.g., the Spectre vulnerability), which may pose significant risks to customers of such clouds.
In the case of Spectre, a bad actor sharing a server with another tenant may be able to get a complete readout of all physical memory of that server—including any data stored in memory by or for other customers and worse, any secrets (such as encryption keys) stored in memory.
While barn-door-sized vulnerabilities such as Spectre may be rare, privilege escalation vulnerabilities (in which a bad actor restricted to a VM gains control of the hypervisor and with it control of other customer's VMs), may be far more common. Both types of vulnerabilities are exacerbated by the shared nature of today's public clouds.
Some cloud providers offer dedicated compute instances, in which CPU and memory are not shared, for example "dedicated instances" at Amazon AWS. However, storage and network is still shared between tenants, which retains the risk of noisy neighbor issues and also potential data disclosure between tenants due to bugs or vulnerabilities in the storage layer.

Dynamic allocation of compute resources at a recovery site


A choke having a trim that includes a wedge-shaped member (“wedge”) and a cage with an opening for receiving the wedge. The wedge includes a first surface and a second surface that is angled with respect to the first surface. As the wedge is positioned into the opening of the cage, the space between the second surface and a third surface inside the opening forms a throttling orifice that restricts the flow of fluid. The size of the throttling orifice is variable depending on the position of the wedge relative to the cage. The trim can provide a positive shut-off point that is separate from the throttling area.

This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the presently described embodiments. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present embodiments. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.
In order to meet consumer and industrial demand for natural resources, companies often invest significant amounts of time and money in searching for and extracting oil, natural gas, and other subterranean resources from the earth. Particularly, once a desired subterranean resource is discovered, drilling and production systems are often employed to access and extract the resource. These systems may be located onshore or offshore depending on the location of a desired resource.
Such systems generally include a wellhead assembly through which the resource is extracted. These wellhead assemblies may include a wide variety of components that control drilling and/or extraction operations. Such components may include one or more production trees (often referred to as "Christmas trees"), control modules, a blowout preventer system, and various casings, valves, fluid conduits, and the like, that generally facilitate the extraction of resources from a well for transport to the surface. In some applications, trees may also be used to inject materials, such as water and/or long chain polymers, into a well. As can be appreciated, production trees often include certain elements for flow monitoring and control, such as choke valves (often referred to as a "choke"), pressure regulators, and flow meters, as well as chemical injection metering valves, various sensors, and so forth.
During resource extraction, the flow rate of resources extracted from a well may be regulated using flow control devices, such as the above-mentioned choke. Chokes generally control flow rate by using an adjustable choke trim to create a restriction in a flow path, thus throttling the flow. The choke trim may include both a movable component and a fixed component, such as is the case with conventional needle and seat trims (sometimes called gate and seat trims). For example, in this case, the needle may be coupled to an actuator that is able to vary the position of the needle relative to the seat. Accordingly, the restriction provided by the choke trim in this case is variable and depends on the position of the needle relative to the seat. For example, the degree of flow restriction may increase as the needle is moved closer to the seat and may decrease as the needle is moved further away.
The aforesaid needle and seat trim configuration has, however, certain drawbacks. For instance, needle and seat trims have a relatively small throttling area (e.g., a circular region between the needle and seat). Generally, erosion is most heavily concentrated at this throttling point and, therefore, trims having small throttling areas, such as needle and seat trims, tend to be affected by erosion more quickly. Further, when fluid flows through the restriction created by the trim, the fluid velocity increases and accelerates while pressure drops. However, if fluid pressure drops quickly to a level that is less than vapor pressure and then subsequently rises quickly to a level greater than vapor pressure, this can cause the sudden formation and collapse of bubbles, known as cavitation. Cavitation may cause significant wear to the choke and adjacent/associated components.


The present invention relates generally to the generation and characterization of anti-MUC18 monoclonal antibodies. The invention further relates to the use of such anti-MUC18 antibodies in the diagnosis and treatment of disorders associated with increased activity of MUC18, in particular, tumors, such as melanomas.

1. Field of the Invention
Embodiments of the present invention concern antibodies binding MUC18 antigen as well as methods and means for making and using such antibodies.
2. Description of the Related Art
MUC18 is a cell-surface glycoprotein originally identified as a melanoma antigen, melanoma cell adhesion molecule (MCAM), whose expression is associated with tumor progression and the development of metastatic potential. MUC18 is a 113 kDA cell surface integral membrane glycoprotein composed of a signal peptide, five immunoglobulin-like domains, a transmembrane region, and a short cytoplasmic tail (Lehmann et al., Proc Natl Acad Sci USA, 86(24):9891–5 (1989)).
MUC18 is a member of the immunoglobulin superfamily and has significant sequence homology to a number of cell adhesion molecules of the Ig superfamily (Lehmann et al., Proc. Natl. Acad. Sci. USA, 86:9891–9895 (1989)), including BEN (Pourquie et al., Proc. Natl. Acad. Sci. USA, 89:5261–5265 (1992)), neural-cell adhesion molecule (N-CAM) (Owens et al., Proc. Natl., Acad. Sci. USA, 84:294–298 (1987)), myelin-associated glycoprotein (MAG) (Lai et al., Proc. Natl. Acad. Sci. USA, 84:4337–4341 (1987)), deleted in colorectal cancer (DCC) (Hedrick et al., Genes Devel, 8(10):1174–83 (1994)), and gicerin (Taira et al., Neuron, 12: 861–872 (1994)). The expression of MUC18 has been detected in relatively limited spectrum of normal human tissues and in a variety of malignant neoplasms. In normal adult tissues, MUC 18 is expressed on endothelial cells, smooth muscle cells (Shih et al., Lab. Invest., 75:377–388 (1996);Sers et al., Cancer Res., 54(21):5689–94 (1994)), a subpopulation of activated T lymphocytes (Pickl et al., J. Immunol., 158:2107–2115 (1997)) and intermediate trophoblasts (Shih et al., Lab. Invest., 75:377–388 (1996)). MUC18 is also expressed on a variety of malignant neoplasms including smooth muscle neoplasms (Leiomyomas and leiomyosarcomas), tumors of vascular origin (angiosarcomas and Kaposi's sarcomas), placental site trophoblastic tumors, choriocarcinomas and melanomas (Shih et al., Clinical Cancer Res., 2:569–575 (1996); Holzmann et al., Int. J. Cancer, 39:466–471 (1987)). The expression of MUC18 correlates directly with the metastatic potential of human melanoma cells (Bar-Eli, M., Cancer Metastasis, 18(3):377–85 (1999)).
A number of studies have identified MUC18 as a marker of tumor progression and metastasis in melanomas. The expression of MUC18 is absent in normal melanocytes and benign nevi but prominent on many primary melanomas and in most metastatic lesions (Lehmann et al., Proc. Natl. Acad. Sci. USA, 86:9891–9895 (1989); Lehmann et al., Cancer Res., 47:841–845 (1987); Shih et al., Cancer Res., 54:2514–2520 (1994)). Importantly, MUC18 expression correlates well with tumor vertical thickness and metastasis formation, and greater than 80% of metastatic lesions express MUC18 (Lehmann et al., Proc. Natl. Acad. Sci. USA, 86:9891–9895 (1989); Xie et al., Cancer Res., 57:2295–2303 (1997); Sers et al., Proc. Natl. Acad. Sci. USA, 90:8514–8518 (1993); Lehmann et al., Cancer Res., 47:841–845 (1987); Shih et al., Cancer Res., 54:2514–2520 (1994). A diagram depicting the expression of MUC18 with respect to other known molecular lesions in human melanoma is presented in FIG. 1.
The expression of the transcription factors ATF-1 and CREB is upregulated in metastatic melanoma cells. However, how overexpression of ATF-1/CREB contributes to the acquisition of the metastasis is unclear. CREB/ATF-1 may play an essential role in invasion by regulating the CRE-dependent expression of the adhesion molecule MUC18 and metalloproteinase MMP-2 (Jean et al., Mol. Cell Biochem., 212(1–2):19–28 (2000)) which belongs to the MMP family known to contribute to cancers and to have a role in tumor invasion, angiogenesis, and metastasis. Tumor cells are believed to utilize the matrix degrading capability of MMPs to spread to distant sites, and once the tumor cells have metastasized, MMPs are thought to promote the growth of these tumor cells. The role of MUC18 in melanoma tumor progression is not completely understood, but may include a role in one or more steps in the metastatic process possibly by affecting MMP-2 activation or cell migration.
The analysis of human melanoma cell lines showed a positive correlation of MUC18 expression with the ability of cells to produce metastases in nude mice (Johnson et al., Cancer Metastasis Rev., 18:345–357 (1999)). The generation of tumorigenic variants from a non-tumorigenic melanoma cell line was reported to be accompanied by induction of MUC18 expression (Luca et al., Melanoma Res., 3:35–41 (1993)). Expression of MUC18 on MUC18-negative human melanoma cell lines increased their tumorigenicity and enhanced their metastatic capability in experimental tumor models (Xie et al., Cancer Res., 57:2295–2303 (1997); Bani et al., Cancer Res., 56:3075–3086 (1996)). Finally, inhibition of MUC18 expression in metastases using genetic suppressor elements of MUC18 cDNA led to a decrease of the tumorigenic phenotype in nude mice (Styamoorthy et al., Oncogene, 20:4676 (2001)).
Although the function of MUC18 is not fully understood, several studies have demonstrated a role for this protein in mediating cell-cell and cell-matrix interactions by binding to an unidentified ligand (Shih et al., Cancer Res., 57:3835–3840 (1997); Johnson et al., Int. J. cancer, 73:769–774 (1997)). The expression of cell adhesion molecules which mediate cell-to-cell or cell-to-matrix interactions is a tumor cell property that is essential for metastases. Accordingly, MUC18-transfected melanoma cells showed increased homotypic adhesion, increased attachment to human endothelial cells, and increased invasion through Matrigel-coated filters suggesting a role in tumor invasion and trans-endothelial migration (Xie et al., Cancer Res., 57:2295–2303 (1997)). Importantly, anti-MUC18 antibodies were able to inhibit these functions in the MUC-18-transfected cells (Xie et al., Cancer Res., 57:2295–2303 (1997)).
Accordingly, there is a great need for anti-MUC18 antibodies that are able to inhibit the biological function of MUC18, most importantly cell proliferation and growth which may be essential to tumor progression and metastasis. Such antibodies would likely interfere with the inherent ability of MUC18 to mediate cell-cell and cell-matrix interactions. The inhibition of such activity may be possible with a monoclonal antibody targeted to MUC18. The ability to affect the progression of tumor cells expressing MUC18 on the cell surface may prove to be a treatment for patients with tumors or of use for prevention of metastatic disease in patients with such tumors.

This patent is subject to a terminal disclaimer.

Use of antibodies against the MUC18 antigen


A tailgate locking system, includes a tailgate pad body for mounting on a tailgate of a vehicle, including at least one bicycle holder structure, a first lock cable, a cable lock device and a lock enclosure, such that the at least one bicycle holder structure is configured to detachably secure the bicycle, such that the first lock cable is extendable through a frame of the bicycle, such that the bicycle is securely locked to the tailgate pad body.

Systems for mounting bicycles on a back of a vehicle are well-known and in common usage.
However, such systems generally do not have effective locking mechanisms, and are therefore vulnerable to thieves who may be able to quickly remove bicycles.
In conventional tailgate pad systems, users may only lock the tailgate to the car which allows for theft of the bicycle, since only a strap is holding the bicycle in place. Therefore, users will have to separately chain the bicycle, using a separate cable lock.
As such, considering the foregoing, it may be appreciated that there continues to be a need for novel and improved devices and methods for mounting and locking bikes on the tailgate of a pickup truck.


A hammock style campers' toilet seat for suspension between trees. The toilet seat includes a web of support straps for lending longitudinal and lateral strength to the seat, and a resilient stiffener ring running about the toilet opening for lending stiffness to the relatively flexible seat about the toilet opening.

The present invention relates to toilet seats and, more particularly, to hammock style toilet seats that are strung between two trees for use by campers.
The majority of state and national parks have conventional bathroom facilities. Even wilderness areas such as the Boundary Waters in northern Minnesota and Isle Royale National Park in Michigan have outhouses in relatively remote areas in an effort to preserve campsites utilized by literally thousands of people.
However, even taking into account the park facilities now available, no comfortable toilet means exists for the backpacker, canoeist, or cyclist who may travel to and set up camp in remote regions unmanaged by state or federal park authorities. To answer Mother Nature's call, such a camper may squat, lean against a tree, or tie two to three limbs in parallel fashion between two trees to form a toilet seat of a general L-shape in section.


A method for restoring system configuration information of a network attached storage includes the steps of: setting system configuration information of an network attached storage as a backup file; registering an interrupt handler; pressing down an input key (16) to turn off a power switch (K1) and generate an interrupt signal; invoking the interrupt handler to process the interrupt signal and returning interrupt GPIO information; determining whether an operating system receives the interrupt GPIO information from the interrupt handler; sending a periodical voltage to a second pin (P2) for blinking a LED (L1) if the operating system receives the interrupt GPIO information from the interrupt handler; invoking the backup file to restore the system configuration information of the network attached storage; and sending a high voltage command to the second pin for powering off the LED, which indicates that the system configuration information has been restored.

1. Field of the Invention
The present invention generally related to methods for restoring system configuration information of a network attached storage.
2. Description of Related Art
Most network attached storage (NAS) devices are embedded systems. NAS generally refers to a data storage element or device that is connected to a network allowing access to computers on the network, thus providing more storage space for users.
The NAS often resides in a machine that is expected to run continuously for years without errors. Therefore software for NAS is usually tested more thoroughly than general purpose operating systems or applications software. When systems errors or other critical errors occur in the NAS, system configuration information of the NAS may be destroyed or altered. The current method for restoring the NAS is to reload new system configuration information on a Flash ROM of the NAS. However, the current method for restoring the NAS has disadvantages, such as some data of the original system configuration information are lost because the new system configuration information is not the same as the original system configuration information.
What is needed is a method for restoring a network attached storage, which can restore system configuration information of the NAS.

Method for restoring system configuration information of a network attached storage

Hong Fu Jin Precision Industry (ShenZhen) Co., Ltd.


A paint container and brush holder made as a unitary mold structure having a built-in paint brush holder compartment and a stationary handle, and at least one tilted side brush holder wall with a bottom with lower paint drain holes. A lower paint reservoir with a substantially opened top may have four or three joined walls and a bottom. With three joined side reservoir walls, a triangular configuration is formed while the four side walls version forms either a rectangular or square configuration. In either embodiment paint from any stored brush in the brush holder compartment drains through lower compartment holes into the lower reservoir. Tilted walls in the brush compartment may be used to rest the brush against them or to wipe off any excess brush paint which then gores into the brush holder's drain holes. A pour spout molded into the intersecting walls of the reservoir, allows any unused paint to be put back into its original shipping paint can after work is completed. By storing and transporting the paint and its paint brush with this unitary structure, there is a lessen chance for paint spillage during transport.

Painters who used brushes often spill paint when moving the brush and its paint container to different location. This is especially true when going up and down ladders when the users concentration is divided between staying on the ladder and keeping the brush and paint container from dripping paint. The semi-circular thin wire bail wire handle typical found on many paint cans or containers is pivotally attached to the can its ends adding providing added degree of movement which adds to the balancing act required as the user moves the container from place to place. To compensate for these concerns attachments and accessories usable with paint containers have been designed that seek to reduce or eliminate the possibility of the spillage of paint as the container is moved. Each such improvement provides a degree of success. However, none provides the multiple convenience of a paint container that has an easy to carry stationary handle, a built-in brush holder with its own tilted excess paint drain that communicates with lower reservoir and an easy to pour spout all as more fully described herein.


A device for controlling discharge from a pneumatic enclosure under pressure, in particular for controlling rapid deflation of a tire to a predetermined pressure value after the device has been assembled to a valve fitted to the enclosure, the device comprising a pushbutton for actuating a striker adapted to cooperate with the deflation pin of the valve and slidably mounted in a case which provides a chamber coaxially around the striker for the deflation pin, at least one vent hole being provided for exhausting the gaseous fluid contained in the enclosure to be deflated, and the striker being slidably mounted in a piston-washer received in said chamber and adapted to cooperate with the striker by a wedging action to hold the striker in a position that allows escape of the gaseous fluid contained in the enclosure.

It is known that the mobility and ground-holding abilities of vehicles, both civilian vehicles and military vehicles, depend on the pressure to which their tires are inflated, and that it may be necessary to reduce tire pressure from a normal running pressure, for example when a vehicle needs to cross ground that is sandy, muddy, or the like. The pressure to which the tires are inflated must generally be reduced quickly and also to a well-determined value. For this purpose, proposals have already been made either for systems for adjusting tire pressure under control from a vehicle cabin (which systems are extremely expensive and therefore of limited application), or else for devices that can be operated by hand, as described in French Patent 2 655 703 in the name of the present Assignee, for example. The device described in that document includes a pushbutton for actuating a rod suitable for cooperating with the deflation pin of the valve, which pushbutton is mounted in a sleeve and can be secured thereto by means of a coupling having retractable balls, the sleeve itself being slidably mounted in a case which provides a chamber coaxial with the actuator rod for the deflation pin and which has vent holes pierced through its side wall to discharge the gaseous fluid contained in the enclosure to be deflated. Although the operation of such a device is satisfactory, it is nevertheless still too expensive to be commercially successful, in particular when it is recalled that the civilian or military vehicles to be equipped with the device generally comprise a relatively large number of wheels.
To mitigate this cost drawback, Applicants have investigated the possibility of providing a device which is even simpler that the previously known device, and which like the previous device is hand-operated, and is suitable for obtaining reliable and rapid deflation of vehicle tires under conditions that are quantitatively reproducible.

Device for controlling discharge from a pneumatic enclosure under pressure, in particular for rapid and controlled deflation of a tire


An apparatus protects the mounting area of casing and a locating profile and optionally a sliding sleeve valve and a flow path from the outside of the valve to the annulus when subsequent attachment of an expanded liner is intended and the expanded liner is to be cemented in place. A barrier sleeve, nose, and outer sleeve define a sealed cavity having a loose incompressible material inside that covers the mounting location on the casing. A locating profile and an optional sliding sleeve valve and a flow path from the outside of the valve to the annulus can be provided. The cementing of the casing takes place through the barrier sleeve. After the cementing, the sleeve and nose are drilled out and the incompressible material is removed to the surface with the drill cuttings. A liner is inserted in the casing and is preferably expanded into sealing contact with the mounting location on the casing. After expansion the liner can be cemented. A shifting tool can be run on the expansion string to actuate the sliding sleeve and if necessary to allow for cement to be pumped from the drill string into the annulus through the sliding sleeve.

FIG. 1 is illustrative of the prior techniques of running in casing with a casing shoe 16 near its lower end. If later a tubular is run in and needs to be attached to the casing by expansion, the presence of cement debris in the support area on the casing where the tubular will be attached could prevent a sealed connection from being obtained. One way around that would be to deliver the cement into a shoe mounted below the point at which the liner will be attached later. Another method would be to run brushes and scrapers into the mounting location after cementing to be sure it was clean so that a good seal and support for the tubular subsequently installed can be obtained. However these techniques require significant amounts of time and create an associated cost.
The present invention protects the mounting location on the casing during cementing with a barrier sleeve that covers a recess. The barrier sleeve defines a sealed annular space that contains an incompressible material. This allows the barrier sleeve to be compliant to changes in hydrostatic pressure as the casing is lowered into place. Cementing is done through the barrier sleeve. The barrier sleeve is subsequently drilled out exposing a recess and a locating profile and optionally a sliding sleeve valve. The tubular can then be positioned accurately using the locating profile and a collet mechanism on the expansion tool and expanded in to sealing contact with the casing. Due to the recess, the drift diameter of the tubular after expansion into the recess is at least as large as the casing drift diameter. The entire tubular can be expanded to its lower end and a run in shoe at the lower end of the tubular can be retrieved and removed from the well with the swaging assembly and the running string that delivered it. The sliding sleeve in the casing shoe can be selectively opened and closed with a shifting tool run on the expansion string above the expansion tools, running tool, and the liner to be expanded. Another option is for this sliding sleeve to be located in the liner to be expanded below the upper portion that mounts in the above casing. The port opened and closed by this sliding sleeve can be used to either pump cement into the annulus or to return the wellbore fluid displaced by cement from the annulus into the casing string. When the sliding sleeve is in the casing shoe, to allow for fluid flow between the outside of this port and the annulus below the shoe after the shoe has been cemented with the string to which it is attached an additional outer sleeve is run on the outside of the recess sleeve. This outer sleeve is connected at its lower end to the inner barrier sleeve via a guide nose. The flow path between the outside of the ports and the annulus is opened when the nose is drilled out and under reamed. A cement retainer device is to be located at the bottom of the string preventing cement pumped into the annulus from entering into the expanded liner due to density differences. This retainer device can be the location from which cement is pumped into the annulus or where the wellbore fluid displaced by the cement is returned from the annulus to the inside of the casing string. The cement retainer can be drilled out in a subsequent trip into the hole. These advantages and others of the present invention will be readily appreciated by those skilled in the art from a review of the description of the preferred embodiment and the claims that appear below.

One trip cemented expandable monobore liner system and method


An apparatus and a method using the apparatus are described for the separation by filtration of a solid phase and a liquid phase from a sludge. A pressure is exerted on the sludge with the aid of a piston in a filtration chamber having a filter. The filter is extracted from the chamber and the surface of the filter is swept using a scraper device. The invention can be used for the treatment of liquid manure.

The present invention relates to an apparatus for the separation by filtration of a solid phase and a liquid phase from a sludge, slurry, or suspension, a method for separation by filtration which can be employed in the said apparatus, and the use of the said apparatus for the treatment of liquid manure. The generic term "sludge" will be used hereinbelow to denote any suspension or dispersion of a particulate solid phase in at least one liquid phase.

Separation of sludge from liquid by piston-aided filtration


A coupling member for incorporation in a torque-transmitting drive train comprises a tube and at least one flange at at least one end of the tube. The tube and flange consist of fiber-reinforced plastic. In order to permit a simpler manufacture and an improved selection of strength and load-carrying properties in adaptation to different conditions of use, the tube and the flange are separately prefabricated and are adhesively joined to and by a sleeve.

1. Field of the Invention
This invention relates to a coupling member for incorporation in a torque-transmitting drive train, which coupling member comprises a tube and at least one flange at at least one end of said tube, wherein said tube and flange consist of fiber-reinforced plastic.
2. Description of the Prior Art
Coupling members made of fiber-reinforced plastic have already proved satisfactory because when used to connect the two halves of a shaft coupling or as a shaft member in a drive train they will not only ensure a satisfactory transmission of torque owing to the special course of their reinforcing fibers but owing to the flexibility of their diaphragm-like flanges they can adapt themselves to axial relative movements of the moving members which are coupled. Beside, the plastic material of the coupling member provides for an effective sound insulation, by which a transmission of structure-borne sound is prevented. As is apparent from EP-Al-0 413 677 the tube and flange of the known coupling member constitute in integral fiber-reinforced plastic body and this involves a considerable manufacturing expenditure. Besides, it is not possible to achieve a perfect adaptation of the reinforcing fibers as regards their course, density and stratitication to the load conditions and adapting movements which are to be expected because the fibers extend continuously from the tube to the flanges so that the arrangement of the fibers in the flange and tube depend on each other to a certain degree.

Geislinger & Co. Schwingungstechnik Gesellschaft m.b.H.


Compositions comprising a mixture of at least two types of particles wherein a) the first type of particles comprise dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; and b) the second type of particles comprise at least one pharmaceutically acceptable organic acid, use of said compositions in the reduction of the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and/or in the prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery and processes for the preparation of said compositions.

Atrial fibrillation is the most common cardiac arrhythmia which is characterized by abnormal heart rhythm. It is considered to be a common cause of irregular heart beat and can cause stroke and other systemic embolic events, eventually leading to death.
It has been seen that the incidence of atrial fibrillation increases with age and nearly 6% of individuals over the age of 65 are affected while the prevalence is about 8% in individuals over the age of 80. The lack of organized cardiac contractions in atrial fibrillation generally results in some stagnant blood in the left atrium or left atrial appendage. This lack of movement of blood leads to thrombus formation or blood clotting. Patients with atrial fibrillation are therefore at greater risk of developing clots which increases the risk of stroke and other systemic embolic events. Since the consequence of stroke or systemic embolism is devastating, a primary aim of therapy for atrial fibrillation is to reduce the risk of arterial thrombus formation and thromboembolism. Anticoagulants such as warfarin are mainly used in case of atrial fibrillation along with other medications such as beta blockers and calcium channel blockers or some noninvasive rhythm control methods. Though anticoagulation therapy with warfarin has been shown to significantly reduce the incidence of stroke or systemic embolism, its use is found to be cumbersome due to multiple diet and drug interactions, chances of hemorrhage which are difficult to manage, requirement of frequent laboratory monitoring etc. Use of a newer safe and effective anticoagulant is therefore necessary.
Direct thrombin inhibitors, is another class of anticoagulants that act by directly inhibiting the enzyme thrombin and are expected to replace heparin (and derivatives) and warfarin in various clinical scenarios. Thrombin, a serine protease protein formed by proteolytic cleavage of prothrombin, converts soluble fibrinogen into insoluble strands of fibrin and further catalyzes many other coagulation-related reactions. Direct thrombin inhibitors inhibit thrombin including fibrin-bound thrombin, thereby delimiting thrombus growth, provide predictable anticoagulant responses because they are not bound to plasma proteins and have no drug-drug interactions. Depending on their interaction with the thrombin molecule, there are bivalent as well as univalent types of direct thrombin inhibitors, with some being in clinical use, while others undergoing clinical development.
Dabigatran is a potent, reversible, univalent direct thrombin inhibitor. It reduces the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. It is also useful in primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Dabigatran inhibits free thrombin, fibrin-bound thrombin and thrombin-induced platelet aggregation. Dabigatran was first disclosed in WO98/37075, which claimed compounds with a thrombin-inhibiting effect and the effect of prolonging the thrombin time, under the name 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino) phenyl]aminomethyl]benzimidazol-5-ylcarboxylic acid-N-(2-pyridyl)-N-(2 ethoxycarbonylethyl)amides.
Dabigatran is currently available as dabigatran etexilate mesylate (DEM) under the brand name Pradaxa® from Boehringer Ingelheim as immediate release oral capsules of 75 mg and 110 mg (in Europe) and 75 mg and 150 mg strengths (in the United States) to be administered twice daily. DEM is a salt form of the prodrug dabigatran etexilate which after oral administration is absorbed and converted to dabigatran by esterase-catalysed hydrolysis in the liver. DEM is a yellow-white to yellow non-hygroscopic powder that exists in two anhydrous polymorphic forms, Form I and II, which are described in WO 2005/028468. The aqueous solubility of DEM is strongly pH dependent with rather high solubility in acidic media and very poor solubility in neutral and basic media while solubility in water is 1.8 mg/mL. The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately about 3-7% and elimination half life is 12-17 hours. DEM is BCS Class II drug, indicating poor aqueous solubility but good membrane permeability. DEM is stable in the solid state and not sensitive to light irradiation but it predominantly undergoes degradation by hydrolytic pathways in the presence of moisture. It is also acid sensitive.
Due to these physicochemical and biopharmaceutical properties of DEM, some attempts have been made to provide compositions of DEM that are stable and/or provide desirable in vitro release and bioavailability.
U.S. Patent Application 2006/0183779A1 describes pharmaceutical compositions of DEM for oral administration in the form of pellets comprising (a) substantially spherical core material comprised of one or more pharmaceutically acceptable organic acids with a water solubility of >1 g/250 ml at 20° C. such as tartaric acid; and (b) an active substance layer containing one or more binders and optionally a separating agent, that encloses said core material. The separating agent layer or insulating layer separates the acid core from the active substance containing layer. The layer of active substance may in turn be enclosed in a coating which increases the abrasion resistance and shelf life of the pellets. Such layered pellets are later filled into hard capsules. However, the process of preparing layered pellets is cumbersome, time consuming and uneconomical.
U.S. Patent Application 2005/0038077 discloses a tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof; one or more pharmaceutically acceptable organic acids with a solubility in water of >1 g/250 ml at 20° C. and a pharmaceutically acceptable excipient or filler. However due to the presence of an organic acid in close contact with the active in a tablet composition without any special steps taken to separate the two from each other, can make the active highly susceptible to hydrolysis in the presence of humidity.
The above attempts only provided compositions of DEM, which are either tedious or technologically demanding to prepare or are unlikely to remain stable over the shelf life of the product. Need therefore exists to prepare alternate compositions of dabigatran etexilate that are stable, easy or convenient to prepare, provide the desired in vitro release and bioavailability.
The present inventors after rigorous experimentation provide oral compositions of dabigatran etexilate comprising a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, wherein a) the first type of particles comprise the active agent; b) the second type of particles comprise at least one pharmaceutically acceptable organic acid; and c) optionally at least one type of particles are coated with a protective coating layer. Such compositions are chemically and polymorphically stable, provide desired in-vitro and in-vivo performance and can be prepared by simple, non-tedious and cost-effective process. In particular, the compositions of the present invention provide a quick dissolution particularly at earlier time points as compared to formulation having one type of particles/pellets. Such a faster dissolution at earlier time points can ensure availability of more amount of active especially when (a) absorption of the active is rapid with faster Tmax (˜45 minutes-1 hour), (b) significant bioactivation is involved and (c) negligible and variable absorption at higher pH.

Oral pharmaceutical compositions of dabigatran etexilate

TOWA Pharmaceutical Europe, S.L. Unipersonal