A transition time is a time from a state where a movable portion has been rotationally displaced in the first direction and stopped to a state where driving portions apply the physical action forces to the movable portion to rotationally displace the movable portion in the second direction, which is different from the first direction, and the movable portion reaches a final displacement position. An elastic force value of the elastic supporting portion and the transition time have such a relationship that when the elastic force value of the elastic supporting portion is equal to a certain value, the transition time takes a local maximum value. The elastic force value of the elastic supporting portion is equal to or less than the certain value at which the transition time takes the local maximum value.

1. Field of the Invention
The invention relates to a micro-electro mechanical device, a micro-electro mechanical device array, a light modulation device, a micro-electro mechanical light modulation device, a micro-electro mechanical light modulation device array, and an image forming apparatus using the same.
2. Description of the Related Art
In recent years, micro-electro mechanical devices which electrically displace and move a micro-mechanical device in the order of μm have been developed briskly because of rapid advancements in MEMS (Micro-Electro Mechanical Systems) technology. Among micro-electro mechanical light modulation devices which have a light modulation function, there is, for example, a DMD (digital micro-mirror device; made by Texas Instruments Inc.) which can tilt a micro mirror to deflection light (see U.S. Pat. No. 6,618,186 and JP 2002-189178 A (which derive from family patent applications). This device exercises an electrostatic force on a movable portion, which is tilted to one side by an electrostatic force, in another direction to thereby rotationally displace the movable portion and modulate light in a mirror part of the movable portion. The DMD is used in wide applications, such as a projection display, a video monitor, a graphic monitor, a television and an electrophotographic printer, in the field of optical information processing. Further, application of optical switches to optical communication, optical interconnection (signal connection technology by means of light, such as an interconnection network in parallel computers), optical information processing (information processing by means of optical operation), etc. has been expected.
A transition time (time from a state where a movable portion is tilted to one side to a state where the movable portion is tilted to another side) or a response speed (speed when a movable portion in a state where the movable portion is tilted to one side is tilted to another side) of a movable portion of a rotational system device of the related art such as the DMD, is determined by the balance among (i) the inertia moment depending on the structure of the movable portion, (ii) the elastic force of a supporting portion, which supports the movable portion so that the movable portion is elastically deformable, and (iii) the magnitude of a voltage to be applied. Appropriate values are adopted at the time of design.
As for the relation between the transition time T and the supporting-portion elastic force K, as shown in FIG. 20, if the supporting-portion elastic force K becomes small, the transition time T of the device tends to increase because the elastic restoring force of the movable portion decreases. It is important to shorten the transition time in order to increase the responsiveness of the device. Therefore, in order to achieve a desired elastic restoring force, a design has generally been made to adopt the supporting-portion elastic force K, which is not excessively small, i.e., to increase the supporting-portion elastic force K.
However, if the supporting-portion elastic force K is increased in order to shorten the transition time T of the device, it is necessary to apply an electrode voltage against the supporting-portion elastic force K in order to drive the device. Thus, a driving voltage increases. Also, if the driving voltage increases, the electric power for the driving of the device will increase. Accordingly, it would be necessary to make a power supply device larger. For this reason, there is a trade-off relation between the followings. That is, in order to control the device in power-saving driving, the transition time becomes long, which leads to sacrifice of high-speed driving, and in order to control the device in high-speed driving, the supporting-portion elastic force K will increase, which leads to sacrifice of the power-saving driving.
Further, even if the supporting-portion elastic force K is increased, the amount of change in the transition time T is slight. Also, even if the supporting-portion elastic force K is increased to shorten the transition time T, a large amount of change in the transition time T cannot be expected in actuality.

Micro-electro mechanical device, micro-electro mechanical device array, light modulation device, micro-electro mechanical light modulation device, micro-electro mechanical light modulation device array and image forming apparatus using the same


A method for setting a bit determination threshold for determining the logic state of a bit in a data bit stream of an NRZ (non-return-to-zero) signal in a GMSK (gaussian minimum shift keying) communication system includes the step of sensing the occurrence of a "flat top" bit in the data bit stream, which signifies the occurrence of a first string of successive same state bits in the data bit stream, where the bits are in a first logic state, such as logic 1. The average bit amplitude of the information signal corresponding to the "flat top" bit of the first string is determined. The occurrence of a second "flat top" bit in the data bit stream which signifies the occurrence of a second string of successive same state bits which are of an opposite logic state, such as logic 0, is then sensed, and the average bit amplitude of the second "flat top" bit of the second string is determined. The average bit amplitude of the first "flat top" bit of the first string is averaged with the average bit amplitude of the second "flat top" bit of the second string to determine a threshold level which is used in setting a bit determination threshold. A circuit for carrying out this method may be in the form of a programmable DSP (digital signal processor).

1. Field of the Invention
This invention relates generally to digital communications, and more specifically relates to the proper determination of transmitted digital data signals, in particular, non-return-to-zero (NRZ) signals.
2. Description of the Prior Art
It is generally known to set the threshold for determining the state of antipodal information symbols based on averaging the received data, a baseband signal, over a relatively long period of time, for example, 200 bit periods or more. The longer the averaging period is, a more precise threshold may be realized. Such a rule may be suitable for many types of modulation, including frequency shift keying (FSK), quadrature phase shift keying (QPSK), offset quadrature phase shift keying (OQPSK) and minimum shift keying (MSK).
Gaussian minimum shift keying (GMSK) and gaussian frequency shift keying (GFSK) modulation techniques are becoming more prevalent in communication systems because of their resultant increased spectral efficiency. Such modulators are implemented by using a premodulation gaussian low-pass filter in the baseband processor of an MSK or FSK modulator, and to which is provided a balanced NRZ data signal. An example of a GMSK modulator is disclosed in U.S. Pat. No. 4,567,602 to Kamilo Feher.
One of the problems associated with use of a gaussian low-pass pre-filter is that it has a "memory" or energy storage effect such that the swing and, thus, the negative and positive amplitudes of the NRZ received data signal are affected. The effect of the gaussian pre-filter in a GMSK system is shown in FIG. 1. The swing and peak amplitudes of the transmitted signal are clearly affected particularly when successive bits alternate in sign (i.e., polarity).
Over long periods of time, this should not have a deleterious effect on the threshold determination, conventionally done by averaging consecutive bits of the received data stream. But for shorter averaging periods, where the probability of equal antipodal excursions of data decreases, and the probability of equal antipodal excursions of data pattern decrease further, the bit determination threshold may be significantly affected. Thus, the gaussian pre-filter in a GMSK or GFSK modem further limits the ability to accurately determine the threshold over fewer bit periods than is conventionally done.

Method and apparatus for determining the detection threshold for an information signal

Uniden San Diego Research and Development Center, Inc.


The present invention provides a method of fabricating an annular fiber structure, the method comprising the steps consisting in: providing a first fiber sheet made up of substantially unidirectional elements; forming a transverse, first annular sheet by laying the first fiber sheet in alternation in one direction and in the opposite direction between coaxial outer and inner circular rings with the sheets being held at said rings; providing a second fiber sheet made up of substantially unidirectional elements; forming a circumferential, second annular sheet by depositing the second fiber sheet in a circumferential direction between said outer and inner rings; bonding the transverse and circumferential annular sheets to each other; and driving the transverse and circumferential annular sheets in rotation about the axis of the outer and inner rings so as to perform a plurality of complete revolutions in order to obtain a thick annular fiber structure having layers made up by the transverse sheet alternating with and bonded to layers made up by the circumferential sheet. The invention also provides an installation for performing the method.

The invention relates to fabricating three-dimensional annular fiber structures.
A particular field of the invention is fabricating thick annular fiber preforms for constituting the fiber reinforcement of annular parts made of composite material, in particular brake disks, such as disks made of carbon/carbon (C/C) material for airplane brakes.
One usual process for making annular fiber preforms consists in superposing and bonding together two-dimensional plies to build up plates from which the preforms are cut out. Such a process, as described for example in U.S. Pat. Nos. 4,790,052 and 5,792,715, presents the manifest drawback of wasting a large amount of material, which drawback is particularly penalizing when the fibers are relatively expensive, as is the case for carbon fibers or carbon precursor fibers.
Various proposals have been made to avoid that drawback and to obtain a fiber structure directly in a shape that is as close as possible to the desired annular shape. Thus, proposals are made in U.S. Pat. Nos. 6,009,604 and 5,662,855 to make preforms by superposing and bonding together layers formed by braids that have been wound flat to form a helix. U.S. Pat. Nos. 6,363,593 and 6,367,130 propose using a helical cloth wound in superposed turns that are bonded together.
Those techniques require a fiber fabric (braid or helical cloth) to be made that is an intermediate product between the yarns or tows of fiber and the annular preform that is to be made.
In order to avoid that intermediate step, patent document WO 98/49382 proposes forming a disordered mass of fibers on an annular support and bonding the fibers together by needling. Nevertheless, that document is silent about the means that need to be used in practice in order to obtain an annular preform that is satisfactory, at least in terms of uniformity, for use in certain applications where requirements concerning uniformity are very high, as are requirements concerning quality control of mechanical properties, as applies in particular when the preform is for use as an airplane brake disk preform.
US patent document 2005/0172465 proposes forming an annular preform by regular and controlled deposition of short fibers on a rotary annular turntable with progressive needling. It is thus possible to obtain a preform that is uniform, but at the cost of passing via an intermediate step of obtaining short fibers.

Fabricating three-dimensional annular fiber structures


A medical implement dispenser and disposal system is provided. The medical implement dispenser and disposal system comprises an enclosure having a body portion. A dispensing chamber within the body portion is configured to contain medical implements. A collection chamber within the body portion above the dispensing chamber is configured to collect soiled medical implements. The body portion defines an access opening positioned for passage of medical implements from the dispensing chamber and an inlet opening positioned for passage of soiled medical implements into the collection chamber, wherein the access opening is oriented in a forward facing direction and the inlet opening is also oriented in the forward facing direction. A barrier is positioned within the body portion to separate the dispensing chamber from the collection chamber. The barrier limits the passage of soiled medical implements from the collection chamber to the dispensing chamber.

In a hospital, doctor's office or home environment setting, soiled syringes or other medical implements are commonly deposited in a disposal container following their use. Unused, sterile syringes or other medical implements are commonly obtained from a source separate from the disposal container. It is somewhat inconvenient at times, however, to provide a source of unused, sterile medical implements and a separate container for collecting the soiled medical implements following their use. In other words, it is sometimes disadvantageous from a convenience standpoint for medical practitioners to have one location from which implements are obtained and a separate location in which implements are disposed of.
Attempts have been made to overcome this inconvenience. For example, a syringe dispensing and storage container for personal use is disclosed by Erickson in U.S. Pat. No. 6,685,017. U.S. Pat. No. 6,685,017 describes a syringe dispensing and collecting system comprising a multi-functional box and a plurality of unused syringes therein. The multi-functional box facilitates the sequential dispensing of unused syringes from the box, with concurrent facilitation of the safe sequential feeding of used syringes into the box for storage therein. A dividing tray is provided within the box to collect used syringes while simultaneously to provide a blockage between the used syringes and an exit opening.
Nevertheless, there continues to be a need to further develop and improve disposal and collection devices for medical implements.

Medical implement disposal and collection device


The invention is a support stand for a joysticks and a keyboard to be used in connection with the joystick. A support base includes a clamping plate and top knobs for securing the base of the apparatus to a planar surface e.g. a desk. A support tray is held in pivotal connection to the base in connection with an tensioning means for adjusting the angle of the tray in relation to the base. The support base has a pair of raised surfaces, parallel to on another, for supporting a standard computer keyboard in a vertical position to position the keys of the keyboard in positions more accurately reflecting aircraft controls and other computer simulations.

1. Field of Invention
The invention relates to the field of home computers and accessories for supporting keyboards and joysticks. In particular, the invention is a support stand with a base for attachment to a desk and a planar support tray for supporting a joystick beyond the edge of the desk at various angles to the support base. The base itself supports the computer keyboard in a vertical position in order to make the various keys more accessible for computer simulations, computer games, etc.
2. Description of the Prior Art
While there are stands for supporting joysticks, none that applicant is aware of are able to support joysticks beyond the edge of the desk in a variety of angled positions vis a vis the support base. Nor are there any supports that applicant is aware of for supporting a key board in a vertical position for realistic positioning of the keys in a computer simulation.

Pivoting joystick and keyboard support stand


A rigid-flex printed circuit board includes an inner circuit substrate, two adhesive sheet layers formed on the inner circuit substrate, two shielding structures, and two outer circuit layers. The inner circuit substrate is divided into a flexible area, a first and second rigid area. Each shielding structure includes a copper layer, a metal seed layer formed on the copper layer, a flexible dielectric layer formed on the metal seed layer, and a backing adhesive sheet layer formed on the flexible medium layer. The backing adhesive sheet layer is pressed on the adhesive sheet layer and the inner circuit substrate located in the flexible area. Each outer circuit layer is formed on the copper layer, located in the first rigid area and the second rigid area and electrically connected to the inner circuit substrate.

The rigid-flex printed circuit boards are being used extensively within the printed circuit board industry. The rigid-flex printed circuit board includes a flexible area and at least one rigid area. A break is generated between the flexible area and the rigid area. When a shielding film of silver paste conductive cloth is formed on the flexible area and the rigid area of the rigid-flex printed circuit board, the shielding film may be at risk of being damaged. Furthermore, the bonding of the shielding film may requires manufacturing processes such as punching, pasting, pressing, tearing the protective film, and baking, all of which may increase a manufacturing cost of the shielding film. Outer layer circuits of the rigid-flex printed circuit board are formed by tenting process, which may not meet the requirements of the Co-design requirements of power supply (thick copper and high current) and signal processing (thin wire).
Therefore, there is room for improvement in the art.

Rigid-flex printed circuit board and method for manufacturing the same

QING DING PRECISION ELECTRONICS (HUAIAN) CO., LTD


A video signal processing apparatus includes a time-division multiplex circuit and a multi-display circuit. A video signals outputted from a first A/D converter included in the time-division multiplex circuit is applied to a memory included in the time-division multiplex circuit and a further memory included in the multi-display circuit. A video signal outputted from a second A/D converter included in the multi-display circuit is also written into the further memory. Then, video signals read-out from the further memory are outputted from a plurality of monitor screens. Since the video signal outputted from the first A/D converter is applied to the further memory, it is possible to increase a renewal speed of the monitor screens with no additional A/D converters in the multi-display circuit.

1. Field of the Invention
The present invention relates to a video signal processing apparatus. More specifically, the present invention relates to a video signal processing apparatus which includes a time-division multiplex circuit for multiplexing a plurality of video signals so as to record the plurality of video signals by a video tape recorder, and a multi-display circuit for simultaneously displaying a plurality of images on a plurality of monitor screens.
2. Description of the Related Art
In the conventional kind of video signal processing apparatus 1 shown in FIG. 11, a plurality of video signals from cameras 0 to 15 are applied to switches 2a and 2b included in a time-division multiplex circuit 1a and switches 2c and 2d included in a multi-display circuit 1b such that any video signals are selected by control signals "cmfx", "cmfy", "cmmx" and "cmmy" outputted from switch control circuits 3a and 3b. Video signals selected by the switches 2a and 2b are converted into digital video signals by A/D converters 4a and 4b, and then inputted to memories 5a and 5b, each of which has a memory capacity equal to one field, and portions of the video signals, each of which is equal to one field, are written into the memories 5a and 5b, respectively. The video signals read-out from the memories 5a and 5b are multiplexed by a multiplexer 7a, whereby a time-division multiplex video signal is obtained.
In contrast, the video signals outputted from the switches 2c and 2d and converted into digital video signals by A/D converters 4c and 4d are written into any areas of a plurality of memory formed in memories 5c and 5d through selectors 6c and 6d. Then, sixteen (16) video signals read-out from the memories 5c and 5d are outputted to a monitor (not shown) through a multiplexer 7d and a D/A converter. Therefore, sixteen video images are simultaneously displayed on sixteen monitor screens in the monitor.
The switch control circuits 3a and 3b have the structure as that shown in FIG. 12. A reference pulse "vd" is inputted to respective counters 8a and 8b as an enable signal. Count values incremented by the enable signals are outputted from the counters 8a and 8b as control signals "cmfb" and "cmmb", and the control signal "cmfb" is applied to latch circuits 9a and 9b, and the control signal "cmmb" is applied to latch circuits 9c and 9d. Each of the latch circuits 9a to 9d is constituted by D-type flip-flop circuits of four (4) bits, and the control signals "cmfx", "cmfy", (commx) and "cmmy" which control the switch circuits 2a to 2d are outputted from the latch circuits 9a to 9d, respectively.
A timing chart of an operation according to the related art is shown in FIG. 13. The switch control circuit 3a outputs the control signals "cmfx" and "cmfy" which are incremented by two (2) at every two fields and have a phase difference equal to one field, as shown in FIGS. 13(D) and 13(H). Accordingly, the video signals shown in FIGS. 13(I) and 13(J) are outputted from the A/D converters 4a and 4b, and written into the memories 5a and 5d. The video signals read-out from the memories 5a and 5b are multiplexed by the multiplexer 7a, and therefore, the time-division multiplex video signal that the respective video signals are changed at every one field as shown in FIG. 13(K) is outputted from an output terminal.
In contrast, the switch control circuit 3b included in the multi-display circuit 1b also outputs the control signals "cmmx" and "cmmy" which are incremented by two (2) at every two field and have a phase difference equal to one field, as shown in FIGS. 13(M) and 13(N). Accordingly, the video signals outputted from the A/D converters 4c and 4d at timings shown in FIGS. 13(O) and 13(P) are written into the memories 5c and 5d, and then, the sixteen video signals are read-out from the memories 5c and 5d. Therefore, the monitor screens corresponding to the video signals shown in the FIG. 13(Q) are renewed.
However, since a renewal speed of the monitor screens depends on the number of the A/D converters provided in the multi-display circuit, it is necessary to increase the number of A/D converters in order to increase the renewal speed.


An anal patch comprising an absorbent pad (3) in a shape with two substantially parallel flat surfaces and a contact surface perpendicular to the flat surfaces, the area of the contact surface being smaller than each of the two parallel flat surfaces, an adhesive part, comprising an adhesive coated backing layer (4), having a central aperture (8) wherein at least a part of the contact surface of the absorbent pad is aligned with the aperture of the adhesive part.

1. Field of the Invention
The invention relates to an anal patch for handling low level incontinence and soiling from the anal area.
Following colorectal cancer treatment, after giving birth or due to otherwise induced or occurring partial loss of sphincter control, a fecal incontinent situation can arise requiring management.
The key users of the invention would thus usually be more senior people (and women from after giving birth) of both sexes, typically plus 60 years of age. Low level fecal incontinence is today not adequately addressed in terms of specific devices to help the patient, and mostly homemade solutions are used, like e.g. female hygienic pads are used, cotton pads or toilet tissue.
2. Description of the Related Art
Different non-invasive solutions that can be placed in the perianal area, specifically the perineum and sacral area of the body in order to collect fecal material or soiling output are known in the art. A number of products/solutions have been described in the patent literature, but few besides hygienic pads and alike are available in the market.
From International patent application Ser. No. WO 06/005717 is known a container for collecting excretions, draining collections, purging ostomies or the like. The container comprises an adhesive patch for applying to the perianal area and a tool for application of this in the form of two blades between which spring means are interposed. The adhesive patch is with radial slits.
US patent application Ser. No. US 2005/0182376 A1 discloses an anal hygienic pad in the form of a wedge-shaped absorbent pad for squeezing in between buttocks without the use of adhesive. The system is unreliable as the pad is not secured to the body and may thus displace when the user moves, as well as the pad is rather thick and may cause discomfort.
U.S. Pat. No. 5,695,484 A discloses an anal patch for fecal incontinence. The patch is in the form of an adhesive patch with an absorbent layer, similar to a wound dressing. The patch has the shape of a saddle in order to provide better fit to the perianal area. The patch may be difficult to apply correctly and without contaminating the users hand, as well as stress may be built up in the patch while the user moves and cause discomfort and/or leakage.
Thus there is still a need for an anal patch or dressing being easy to apply, comfortable and with good adhesiveness and safety when moving around. The anal patch of the present invention fulfills these and other objects.


A pulley stud for a window regulator is provided. The pulley stud having: an upper head portion; a shaft portion; a first mounting portion; and a second mounting portion, wherein the first mounting portion has an anti-rotation portion located on a portion of the periphery of the first mounting portion.

Various embodiments of the present invention relate to a cable pulley fastener and method of fastening a cable pulley to a window regulator of a vehicle.
In addition, embodiments of the present invention provide improvements in the formation and mounting of window regulator systems. Still further, other embodiments of the present invention provide improved mounting structures and methods for formation and attachment of window regulator systems to a vehicle body.
Actuation of windows, such as vehicle windows, often utilizes window regulator systems for controlling vertical movement of the window. In one configuration, such window regulator systems include one or more window attachments carriers or sliders each slidably engaging a guide rail. The window attachment also includes an attachment feature for attachment of the window to the window attachment and hence the window moves as the attachment slides along the guide rail. In order to facilitate the movement of the window, the window attachment is secured to a drive means, such as a cable, which is driven by a drum rotated by a motor. In operation, as the drum rotates a portion of at least one cable is wound onto the drum while a portion of the at least one cable or another cable is unwound from the drum. Each end of the cable or if two separate cables are employed one end of each of the cables are secured to the window attachment to either pull or allow for (e.g., unwind) slidable movement of the window attachment as the cable drum is rotated by the motor.
Since the cable drum is typically remotely located from the ends of the guide rail the window attachment slides along, pulleys are located near or at the distal ends of the guide rail so that as the cable drum is rotated the applicable force is applied to the window attachment in order to cause it to slide along the guide rail. The pulleys provide rotational support of the cable(s) as is/they are wound and unwound from the cable drum.
However and in view of a desire to simplify securement methods, strength of the system, and overall efficiencies, without adversely affecting performance it is desirable to provide an improved fastener for securement of the pulley to the rail as well as a window regulator with such a fastener.
Accordingly, it is desirable to provide a fastener for securement of the pulley to the guide rail. Still further, it is desirable to provide a method for securement of the fastener to the guide rail as well unique configurations thereof.

Cable pulley fastener and method of fastening a cable pulley for a window lifter of a vehicle


An apparatus for bonding two substrates includes a first roller, a second roller that forms a nip with the first roller, a substrate transport configured to move the first substrate and a second substrate through the nip simultaneously, and a controller. The controller operates the substrate transport to move the first substrate and the second substrate through the nip simultaneously, with a pattern of a hydrophobic material on a first side of the first substrate engaging a first side of the second substrate. The first substrate engages the first roller, which has a higher temperature than the second roller, and the hydrophobic material penetrates the first and second substrates to bond the substrates together.

Paper-based chemical assay devices include a paper substrate, wax that forms fluid channels and other fluid structures in the paper, and one or more reagents. Common examples of paper-based chemical assay devices include biomedical testing devices that are made of paper and perform biochemical assays and diagnostics in test fluids such as blood, urine and saliva. The devices are small, lightweight and low cost and have potential applications as diagnostic devices in healthcare, military and homeland security to mention a few.
Many of the paper-based diagnostic devices are formed from multiple layers of paper that is embedded with chemical reagents and with hydrophobic materials, such as wax or phase-change inks, that form channels to direct the diffusion of a biological fluid through the porous paper to one or more sites where the chemical reagents react with the biological fluid to perform the assay. When properly aligned, the multiple layers of paper enable three-dimensional paths for the fluid to reach the testing sites in the sensor, which enables a larger number of testing sites for different assays to be formed in a device of a given size compared to a two-dimensional arrangement in a single layer of paper. Additionally, some chemicals in the testing device are reactive to air or other environmental contaminants. The multiple layers of paper, with an optional coating of wax or another hydrophobic material, isolate portions of the testing device from the environment to prevent contamination.
Existing biomedical devices that are formed from multiple layers of paper or another substrate use adhesive layers that are interposed between the substrates to adhere multiple substrate layers together. For example, FIG. 6 depicts an exploded view of multiple paper layers 504A-504D that are bonded together with multiple corresponding layers of an adhesive film 508A-508C. Each layer of adhesive film is, for example, a two-sided adhesive tape. The adhesive film layers include holes, channels, and other perforations that enable liquid from one layer substrate layer to pass through the adhesive material to reach another layer of the substrate. For example, a fluid that is applied to the region 520 in the layer 504A passes through a corresponding opening 524 in the adhesive layer 508A to reach a corresponding fluid channel region 528 in the substrate layer 504B.
The separate adhesive layers that are used in the prior art biomedical have drawbacks during the manufacturing process and during use of biomedical sensors. During manufacture, the adhesive layers must be formed with openings that conform to the size, shape, and position of the openings in the two substrate layers that surround the adhesive. Forming the openings and aligning the substrate layers with the adhesive layer increases the complexity of the manufacturing process. During use, the biomedical sensor receives different biological fluids. In some instances, the biological fluids are chemically reactive with the adhesive material in the adhesive layers. The reactions between the fluid and the adhesive may contaminate the biomedical sensor and reduce the accuracy of assay results. Consequently, improvements to the production process and structure of multi-layer biomedical sensors and other multi-layer devices would be beneficial.

System and method for forming bonded substrates


A process is disclosed for preparation of a immunogenic peptide mixture in a single synthesis. The peptide mixture collectively represents the in vivo variability seen in immunogenic epitopes from a pathogen. The mixture is termed a hypervariable epitope construct (HEC). Immunization with a HEC evokes broadly reactive immunity against divergent strains of a pathogen upon which the HEC is based.

Many pathogens, including viruses such as HIV-1 and HIV-2, influenza, hepatitis A/B/C, human papillomavirus (HPV), and dengue, as well as parasites such as malaria and trichinella, can readily alter the amino acid sequence within particular protein epitopes. In view of this behavior and for other purposes, synthetic peptide vaccines are increasingly being explored as alternatives to attenuated or inactivated vaccines. By selection of only those epitopes that confer an effective immunity, epitopes responsible for deleterious immune responses, such as enhancement of disease or T-cell suppression, can be excluded from candidate vaccines. Additionally, as they are chemically defined and lack any infectious material, they pose minimal health risks. Finally, unlike live attenuated vaccines which must be transported and stored at defined, refrigerated temperatures, peptide vaccines are relatively stable and do not require refrigeration, thus making distribution far easier and less costly.
Currently, synthetic peptide vaccines are being evaluated for protection against bacteria, parasites, and viruses. Bacterial epitope vaccines include those directed against Cholera and Shigella. A synthetic vaccine against malaria has undergone phase I and phase II clinical trials in humans. Influenza and hepatitis B viruses represent two viral systems in which synthetic vaccines look especially promising, and there has been much recent interest in synthetic vaccines against human immunodeficiency virus (HIV).
Despite recent advances, synthetic peptide vaccines have been unable to account for envelope or surface protein variability. Several groups have attempted in the past to account for epitope variability using a variety of approaches. One approach to address epitope variability has been described by Tam in U.S. Pat. No. 5,229,490 (Jul. 20, 1993). This process involves conjugating several similar or different epitopes to an immunogenic core by using lysine functional groups and glycine linkers (called dendritic polymers). This process is referred to as a multiple antigen peptide system (MAPS). While highly immunogenic, HIV-based MAPS have not proven to induce broadly reactive antibodies that can recognize divergent strains of virus (Nardelli et al. (1992) J Immunol 148:914–920).
Another early approach involved the identification of 'mimotopes,' which are randomly generated sequences which mimic antigenic epitopes (Lenstra et al. (1992) J Immunol Methods 152:149–157). Using this approach, degenerate oligonucleotides are inserted into bacterial expression vectors, resulting in an expression library of random peptides 6–8 amino acids in length. Those peptides that mimic antigenic epitopes are identified using sera (containing antibodies) from animals or individuals infected with the pathogen of interest. Indeed, this general approach has been used to identify mimotopes that are recognized by sera from HCV-infected individuals (Prezzi et al. (1996) J Immunol 156:4504–4513). However, the peptides are randomly selected and there is a necessity to acquire and analyse sera from infected subjects in order to formulate the mimotope composition.
A further disadvantage to prior art approaches requiring sera from infected individuals is that many infected individuals do not manage to create appropriate anti-pathogen antibodies. Thus, selecting peptides of interest using patient sera could potentially lead to the omission of important antigenic peptides that mimic epitopes against which infected individuals have been unable to mount an immune response.
Using the SIV:rhesus macaque model for HIV infection of humans a, SIV envelope glycoprotein B cell neutralization and T cell epitope has been described and a synthetic immunogen was designed and synthesized based on the hypervariable and highly antigenic epitope of the SIVmac142 envelope glycoprotein (gp130) (Anderson et al. (1994) Vaccine 12:736–740). This synthetic immunogen consisted of a mixture of peptides representing permutations of amino acid substitutions found in SIV envelope gene sequences. Thus, the synthetic immunogen collectively represented all the in vivo variability observed for this particular epitope. Immunogenicity of this synthetic immunogen was evaluated, and it was shown to induce enhanced amounts of antibodies in immunized rhesus macaques with binding to native biological SIV. Furthermore, it enhanced immunoreactivity to divergent epitope analogs. In this and a subsequent publication (Meyer et al (1998) AIDS Res Human Retro 14:751–760) it was demonstrated that this approach could account for epitope variability.
In recent years it has become clear that T cells are degenerate in their recognition of peptide antigens. This discovery has raised concerns that peptides from some foreign antigens may mimic some self antigens and inadvertently lead to the activation of autoreactive T cells and the onset of autoimmune disease. Consequently, there would be a risk of autoimmune disease associated with immunization of animals or human with a mixture of randomly synthesized peptides. Mimotope processes (Lenstra et al. (1992) J Immunol Methods 152:149–157) select a subset of peptides for immunization from a mixture of randomly synthesized peptides using sera from infected animals or humans, and thus reduces the risk of autoimmune disease. However, the synthetic immunogen formulations described above (Anderson et al. (1994) Vaccine 12:736–740; Meyer et al (1998) AIDS Res Human Retro 14:751–760) do not contain completely random mixtures of peptides, as the peptides generated are based on the addition of only a few of the possible 20 amino acids at only some steps of the synthesis reactions. Nonetheless, synthetic immunogenic formulations such as those described in the prior art may contain over 8,000 different peptide antigens. While this process led to an immunogen which evoked broadly reactive immunity, the formulation was too complex to characterize biochemically or immunologically, and immunization of humans which such a compound would carry with it a significant risk of autoimmune disease. Further, without full compositional analysis, regulatory approval of a mixed peptide composition is not likely to be obtained. Full compositional analysis for a mixed peptide composition having hundreds or thousands of different peptides would be extremely time-consuming, and is unlikely to be cost-effective.
Many of the previously described synthetic immunogenic formulations are mixtures of tens of thousands of different peptides. Given that T cells are degenerate in their recognition of foreign antigens, mixtures of peptides this complex pose the risk of containing peptides which mimic self antigens, which upon immunization could induce a pathogenic autoimmune response. Moreover, the complexity of previous synthesis schemes made it difficult if not impossible to chemically define and assess the quality of multiple individual preparations of the same composition.
On this basis, there is a need for a new process for the design of an immunogenic peptide mixture resulting in a less complex formulation than those described in the prior art, while retaining optimum immunogenicity. Such a new process would allow such mixtures to be prepared and analysed for human use. Further, there is a need for development of assays to be run on such a preparation in order to ensure the integrity and antigenicity of the mixture formed in the synthesis reaction.

Immunogenic formulation and process for preparation thereof


A model framework is used to implement the model component of application using a model-view-controller design pattern. The model framework provides built-in functionality that defines a default behavior. Application programming interfaces (APIs) allow an application developer to modify the default behavior of the model framework in a manner that suits the data model of the application.

Unless otherwise indicated herein, the approaches described in this section are not prior art to the claims in this application and are not admitted to be prior art by inclusion in this section.
Business applications typically execute on application servers in the enterprise, using the client computer largely to support only the user interface. Such clients have been referred to as "thin" clients to reflect that virtually all of the business application functionality is provided in the application server. In web-based business applications, some of the business logic has migrated to the client machine, using web interface technology such as web services description language (WSDL), simple object access protocol (SOAP), and the like to support higher levels of functionality on the client.
As the processing power of mobile devices continues to increase, more and more of the business logic is being migrated down to the mobile device. For this reason, mobile devices, such as computer tablets, smartphones, and the like, are sometimes referred to as "rich" clients because of the rich set of features that mobiles device can support in a business application. Placing the business logic on the mobile device creates challenges in the design and implementation of mobile business applications, including secured access to data at the backend servers, data security in the mobile device, integrity of the business data, ensuring data is up to date, and so on.


The in vivo oxidation of lipids and lipid-containing molecules has been discovered to be initiated by the concurrent reaction of such lipid materials with reducing sugars such as glucose, advanced glycosylation endproducts such as AGE-peptides, or a compound which forms advanced glycosylation endproducts, to form materials or particles known as AGE-lipids. AGE-lipids have been implicated in the aging process, the abnormal formation of lipofuscin and in various disease states such as diabetes and atherosclerosis. Diagnostic methods are contemplated, extending in utility from the detection of the onset and course of conditions in which variations in lipid oxidation, AGE-lipid levels, LDL levels, apolipoprotein levels, apolipoprotein receptor binding the like, may be measured, to drug discovery assays. Corresponding methods of treatment and pharmaceutical compositions are disclosed that are based on an active ingredient or ingredients that demonstrates the ability to modulate the levels of all of the foregoing markers of lipid oxidation.

Glucose and other reducing sugars attach non-enzymatically to the amino groups of proteins in a concentration-dependent manner. Over time, these initial Amadori adducts undergo further rearrangements, dehydrations and cross-linking with other proteins to accumulate as a family of complex structures which are referred to as Advanced Glycosylation Endproducts (AGEs). Beginning with the early work of the present applicants and extending to the present, substantial progress has been made toward the elucidation of the role and clinical significance of advanced glycosylation endproducts, so that it is now acknowledged that many of the conditions heretofore attributed to the aging process or to the pathological effects of diseases such as diabetes, are attributable at least in part to the formation of AGEs in vivo.
Advanced glycosylation tends to occur on molecules with long half-lives, under conditions of relatively high sugar concentration, such as in diabetes mellitus. Numerous studies have suggested that AGEs play an important role in the structural and functional alteration which occurs during aging and in chronic disease. Additionally, advanced glycosylation endproducts are noted to form more rapidly in diabetic and other diseased tissue than in normal tissue.
A particular area that has received attention in light of the series of discoveries regarding the relationship of advanced glycosylation of proteins to the etiology of conditions such as diabetes and aging, has been the set of events that coincide in the development of vascular disease. Specifically, the formation of atherosclerotic lesions and plaques is an example of a condition that has been extensively investigated with a view to elucidating the interrelationship, if any, that exists between the oxidation of low density lipoproteins (LDL) and the presence and formation of AGEs.
In this connection, research connected with the phenomenon of protein glycosylation has been extended in scope to a broad variety of biological molecules in an effort to first identify the existence of AGE formation in these diverse compartments, and thereafter, to determine the significance, if any, that may be attributable thereto. It is in this context that the discovery of a reaction of this type involving lipids as defined later on herein (eg. the formation of AGE-lipids), was initially presented in parent Application Ser. No. 07/887,279, referred to hereinabove and incorporated herein.
The formation and existence of AGE-lipids was postulated and observed in the said parent application, and the significance of these materials as markers and actors in the conditions already associated with the presence of AGEs, was likewise noted. As stated therein, AGE-lipids are important biologically. The formation of AGEs on lipids has been observed to begin the lipid oxidation process and thus may render these species more active biologically and chemically, and in particular, more prone to deposition on the interior of blood vessels. It is therefore believed that AGE-lipids may be involved to varying degrees in atherosclerosis, stroke and other vascular disease.
For instance, oxidation of the lipid component of low-density lipoprotein (LDL) results in the loss of the recognition of the apo B component by cellular LDL receptors, and in the preferential uptake of oxidized-LDL(ox-LDL) by macrophage "scavenger" receptors. The enhanced endocytosis of ox-LDL by vascular wall macrophages transforms them into lipid-laden foam cells that characterize early atherosclerotic lesions.
The "family" of AGEs includes species which can be isolated and characterized by chemical structure; some being quite stable, while others are unstable or reactive. AGE-lipids may also be stable, unstable or reactive.
When used with reference to endogenous lipids, AGE-lipid compounds are typically formed non-enzymatically in vivo. However, AGE-lipid compounds can also be produced in vitro by, e.g., incubating a mixture of a reducing sugar and a suitable lipid, e.g., a lipid bearing an amino group, or by other methods in vitro, such as chemical coupling of AGEs and AGE models to biological macromolecules.
The reaction between reducing sugars and the reactive groups of lipids may initiate the advanced glycosylation process. This process typically begins with a reversible reaction between the reducing sugar and the reactive group to form a Schiff base, which proceeds to form a covalently-bonded Amadori rearrangement product. Once formed, the Amadori product undergoes further rearrangement to produce the AGE-modified compound.
Although these reactions occur slowly, lipids may accumulate a measurable amount of AGEs in vivo. The resulting AGE-lipids may reduce the structural and/or functional integrity of organs and organ parts, modify the metabolism, or otherwise reduce or impair host function.
As stated in Parent application Ser. No. 07/887,279, the formation of AGE-lipids is believed to presage atherogenesis and to induce fatty acid oxidation.
Correspondingly, it was disclosed that aminoguanidine, an established inhibitor of protein advanced glycosylation also inhibits AGE-lipid formation.
The parent application also disclosed that aminoguanidine reacts directly with malonyl dialdehyde (MDA)-like fatty acid oxidation products, to inhibit the role that they play in continued atherogenesis. This finding was further confirmed in Picard et al. (1992) Proc. Natl. Acad. Sci. U.S.A., 89:6876-6880, published in August, 1992, and after the filing date of the said parent application. Picard et al. focused their study on the reaction between MDA and apolipoprotein B (apo B), a protein component of LDL, and performed experiments to determine the ability of aminoguanidine to bind preferentially to MDA to prevent its conjugation to apo B. To establish the environment for these experiments, the authors induced lipid peroxidation by incubation with endothelial cells or with Cu.sup.2+. The Picard et al. experiments were cumulative with experiments presented earlier by applicants with respect to this specific mechanism of aminoguanidine action, but are limited by the specific in vitro environment chosen, as the physiological oxidation of lipids to form the reactive aldehydes to which aminoguanidine is confirmed to bind in the context of the present invention, will not occur by the means utilized in the article.
More particularly, in vitro studies suggest that the oxidative modification of lipids proceeds via free radical-mediated oxidation of unsaturated bonds that are present within fatty acid residues (12, 13). Polyunsaturated fatty acids are particularly sensitive to oxidation because methylene hydrogens located between paired double bonds are easily abstracted by radical-catalyzed reactions. Diene conjugation occurs and hydroperoxides form. This is followed by fatty acid decomposition, the formation of reactive aldehydes, and in the case of LDL, the covalent modification of apoprotein residues (12, 14, 15).
The biochemical processes that initiate lipid oxidation in vivo remain poorly understood. Triplet oxygen is a poor oxidant under normal, physiological conditions and significant oxidation of LDL in vitro occurs only after the addition of micromolar concentrations of divalent metals such as copper. Lipid oxidation is prevented completely in these incubations by the inclusion of metal chelators such as EDTA (15). LDL oxidation also occurs in diverse cell culture systems and can be inhibited partially by pharmacological blockade of cellular lipoxygenases (16). The precise role of reactive oxygen species in the oxidative modification of lipids in vivo has not been determined, however. Low trace metal concentrations, the high availability of ligands that form tight coordination complexes with metals, and the abundant anti-oxidant capacity of plasma suggest that metal-catalyzed autoxidation and reactive oxygen species play little, if any role in mediating lipid oxidation in vivo (17-19).
Since the filing of the parent application, further studies have more fully revealed and likewise confirmed the significance of the findings presented therein. Accordingly, it is toward the presentation of these findings and the further elaboration of the various earlier stated embodiments of the invention that the present disclosure is directed.

Glycosylation of lipids and lipid-containing particles, and diagnostic and therapeutic methods and materials derived therefrom

The Picower Institute for Medical Research


In the synthesis of an amide compound through reaction of an acyl fluoride group-bearing compound with an amino compound, a reaction mixture contains the amide compound and hydrogen fluoride or a hydrofluoric acid amine salt. The amide compound is recovered in high purity form by adding an oxide, carbonate or hydroxide of an alkaline earth metal to the reaction mixture to convert the hydrogen fluoride or hydrofluoric acid amine salt to an alkaline earth metal fluoride salt that can be readily removed by filtration.

In the prior art, an amide compound is synthesized from a compound having an acyl fluoride group within a molecule through several routes, for example, by direct reaction of the acyl fluoride group-bearing compound with an amino compound. It is known that this direct reaction proceeds in a quantitative manner. During the reaction, hydrogen fluoride is produced as a by-product. If the amino compound is present in excess in the reaction system, hydrogen fluoride forms a salt with the amino compound.
Separately, another amino compound is added to the reaction system as an acid acceptor if necessary. Hydrogen fluoride can also form a salt with the other amino compound which is optionally added. Then, to remove the salt of hydrogen fluoride with amino compound (hydrofluoric acid amine salt, hereinafter) from within the reaction system and isolate the target amide compound, post-treatment by water washing is generally carried out.
However, some amide compounds produced are not effectively separable from water. Then the prior direct reaction process has the problems that time-consuming many steps are necessary until the target amide compound is obtained, and incomplete purification allows a large amount of hydrofluoric acid amine salt to remain in the amide compound product, which eventually invites a decline of production yield. Even with a target amide compound that can be isolated by distillation, if the removal of hydrofluoric acid amine salt in the preceding step is incomplete, the hydrofluoric acid amine salt will sublimate during the distillation step so that the distilled fraction is contaminated with it. Sometimes, the hydrofluoric acid amine salt will precipitate on a cooling section of a distillation column, clogging the distillation column.
As a means of avoiding these problems, Japanese Patent No. 2,855,081 discloses to add a silazane compound to a reaction mixture resulting from reaction of a compound having an acyl fluoride group within a molecule with an amino compound and containing the amide compound and hydrogen fluoride and/or a salt of hydrogen fluoride with the amino compound, for thereby removing the hydrogen fluoride and/or the salt of hydrogen fluoride with the amino compound.
Although this method is superior to the previous water washing method, it is difficult to remove unreacted silazane compound and partially reacted silazane compounds remaining in the system at the end of reaction, which mostly cause the target amide compound to be colored. The silazane compound used in this method is generally expensive and sensitive to air-borne moisture and thus difficult to handle.
It would be desirable to have an amide compound purifying method capable of recovering an amide compound, from a reaction mixture resulting from reaction of an acyl fluoride group-bearing compound with an amino compound, through simple steps and in a high yield and high purity.


A scanning lens component includes a primary and transverse axis stages and motors. The primary axis motor includes a first coil moving along the primary axis in the first direction along with the primary axis stage and a first magnet configured to move in a second, opposite direction, in response to movement of the first coil a first distance that exceeds a threshold primary axis distance. The transverse axis stage is adjacent and coupled to the primary axis stage and moves along a transverse axis in a third direction. The transverse axis motor includes a second coil for moving along the transverse axis in the third direction with the transverse axis stage, and a second magnet configured to move in a fourth, opposite direction, in response to movement of the second coil along the transverse axis in the third direction a second distance that exceeds a threshold transverse axis distance.

1. Field of the Invention
The present invention relates in general to an ophthalmic laser system, and means to greatly reduce reaction forces in linear or curvilinear stages of the ophthalmic laser system.
2. Description of Related Art
Laser beam delivery systems are used to perform laser vision correction (LVC) procedures, such as PRK or LASIK procedures. Typically, the laser beam delivery system provides a laser beam from a pulsed laser and directs and/or focuses the laser beam at an ablation plane in which the cornea of a patient is located with precision. The laser beam delivery system conditions the beam and scans the beam across the corneal surface in order to ablate small portions of the cornea in a very controlled manner.
Because precision is required in performing LVC procedures, proper alignment is a significant concern. In particular, the laser should be properly aligned to the ablation plane, and the delivery system should be aligned to direct portions of the beam into monitoring equipment used during the procedure. As laser beam delivery systems generally are relatively complex and many systems include numerous moving parts, the slightest movement of certain system components can affect alignment. Realignment of the system components can be relatively difficult and/or time consuming to perform. However, such repositioning is necessary, as misalignment of the beam degrades the quality of the beam over time and/or damages optical components within the system and/or laser cavity (e.g., the laser output coupler).

Scanning lens systems and methods of reducing reaction forces therein


A swing seat configured to be supported by a swing frame includes a seat bottom frame, a seat back frame movably coupled to the seat bottom frame, and a recline mechanism to recline the seat back frame relative to the seat bottom frame. The recline mechanism includes first and second mounts on opposite sides of the seat back frame to movably mount the seat back frame to the seat bottom frame, at least one recline lock associated with at least one of the first and second mounts and configured to lock the seat back frame in at least two recline positions relative to the seat bottom frame, and a recline actuator having a grip intermediate the first and second mounts and movable between an un-actuated position and an actuated position. The at least one recline lock is movable between a locked position to set the recline position of the seat back frame relative to the seat bottom frame and an unlocked position to allow adjustment of the recline position of the seat back frame relative to the seat bottom frame. The recline actuator is coupled to the at least one recline lock such that movement of the recline actuator from the un-actuated position to the actuated position moves the at least one recline lock from the locked position to the unlocked position.

Various types of swings are known. Typically, the swing includes a support frame, a hanger arm or arms pivotally attached to the support frame, and a seat attached to the hanger arm or arms. The swing also can include an electrically powered drive mechanism to move the swing seat in a back-and-forth motion.
Some swings include a seat back recline mechanism. The seat back of these swings can be adjusted to different recline angles relative to the seat bottom so that a caregiver can position the seat in various recline positions, including an upright position, a fully reclined position, or an intermediate position between the upright position and the fully reclined position, depending on the age and needs of the child. Older children may prefer a more upright position, while younger children with less neck control may prefer a more reclined position.
The seat back recline mechanism of one existing swing product includes a bent wire that travels along a slot or pair of slots formed as part of the seat back. The location of the wire in the slot determines the recline position of the swing seat. The wire can be mounted to hanger arms on either side of the seat back or to another suitable structure. To adjust the wire to a different recline location in the slot, a caregiver can use one hand to move the wire and the other hand to support the seat back. These wire arrangements are not intuitive or easy to operate for all caregivers.
A different seat back recline mechanism for a swing seat includes latches positioned on opposite sides of the seat back to engage latch-receiving ribs positioned on the hanger arms of the swing. The ribs correspond to different seat back recline angles. To change the recline angle of the seat back, a caregiver can grip the latches directly and re-position the latches against ribs corresponding to the desired seat back recline angle. This seat back recline mechanism can be awkward to operate for some caregivers.
There is a need for a swing with an improved seat back recline mechanism.


The invention relates to an electrical panel heating device and to a method and a material for the production thereof; the panel heating device is produced by curing a liquid or pasty material, comprising at least one inorganic binding agent, for example cement and/or gypsum, at least one electrically non-conductive additive, for example sand and/or rock flour, and at least one further additive composed of electrically conductive particles, for example carbon fibers and/or trips; after mixing this material in the liquid or pasty state, it is processed to form a product in the form of a panel which is provided with low-impedance contacts for feeding in a current distributed over an panel.

1. Field of the Invention
This invention is directed to an electrical panel heating device and to a method and a building material for the production thereof.
2. Description of the Prior Art
In many buildings, particularly old structures with high-ceilinged rooms, it is often difficult to heat a room to a comfortable temperature, since, especially in southern climes, either there is no heating system at all, or the one that is present is not adequate for cold winter days.
Known heating systems usually are high-priced, are complicated to install and sometimes entail structural modifications. Known panel heating devices are designed, for example, to be disposed under the plaster of a wall and are unsuitable for retrofitting in a finished building.
In addition, many electrical heating devices contain water- or vapor-impermeable films or layers, between which the heating device per se is located. Such heaters prevent the necessary diffusion of water vapor through walls and other structural elements. At times when such heaters are not being operated, e.g. in the summer, damp spots occur. Mold (Aspergillus fumigatus) then forms on such damp walls, ceilings and floors.
From these disadvantages of the described prior art comes the problem initiating the invention, that of creating an electrical panel heating device that is easy and inexpensive to make and install and is, in particular, suitable for being retrofitted into a finished building.

Electrical panel heating device and method and building materials for the protection thereof


A flash controller is adapted to communicate with a host and the flash memory and including volatile memory configured to store a page-block table of logical addresses addressable by the physical addresses. The logical addresses are used by the controller to identify the blocks. The table has an address mapping table and a property value table, the property value table includes property values, each of the property values being increased in value every time a block is written up to a maximum value and being associated with a block of a predetermined group of blocks and indicative of the number of times a block has been written, the property values corresponding to the logical addresses of the address mapping table, wherein the maximum number the property values of the predetermined group of blocks take on is adjustably different than the maximum number the property values of another group of blocks.

1. Field of the Invention
This invention relates to the field of digital systems employing non-volatile (or flash) memory and particularly to wear-leveling memory cells of the flash memory.
2. Description of the Prior Art
Solid state memory or non-volatile memory, in the form of flash, is readily employed in numerous applications requiring saving and retrieving digital information. Some use thereof includes memory sticks, disk drives, personal digital assistants (PDAs) and other digital mobile devices.
NAND flash memory is a type of flash memory constructed from electrically-erasable programmable read-only memory (EEPROM) cells, which are an array of floating gate transistors. NAND refers to the type of gate used in the flash memory. NAND flash memory uses tunnel injection for write and tunnel release during erase operations. NAND flash, which is a type of non-volatile memory, is ideal for storage of digital information in portable devices.
However, NAND flash memory does have limitations. Namely, in flash, digital information or data is stored as binary information, i.e. '1' or '0'. One limitation posed by NAND flash memory is that during storage of data, which occurs during writing to or programming of the flash memory, data that is '1's can only be stored in the flash memory. Data that is '0's cannot be store until erase occurs of the previously-stored data. In fact, when writing from a state of '0' to a state of '1', the flash memory needs to be erased a "block" at a time, which is undesirable as it adversely affects performance by way of efficiency. The reason for the requirement for erasing a "block" at a time is that while the smallest unit for a read or program operation to NAND flash memory is a byte (eight bits) or a word, the smallest unit for erase is a block. A bit of information or data is represented by a '1' or '0'. A block refers to one or more pages of information made of bytes or words and the block is an erasable unit. An exemplary page size is 2,112 bytes, 2024 bytes of which are typically reserved for data and 64 bytes of which are typically reserved for spare. Spare being overhead information, such as address flag, error correction code (ECC) or other non-data information. The structure of a page can be either 4*512+4*16 bytes or 4*(512+16) bytes, the 512 bytes being used for data and the 16 bytes for spare. The structure of a page may be other than the foregoing but essentially similar in the type of information included therein.
Single Level Cell (SLC) flash memory and Multi Level Cell (MLC) flash memory are two types of NAND flash memory. The erase block size of SLC flash is 128K+4K bytes and the erase block size of MLC flash is 256K+8K bytes. Thus, erase operations severely impact performance, particularly, when performed on large capacity memory. Another limitation of NAND flash memory is having a finite numbers of times of erase cycles before it becomes unreliable. The number of erase operations that may be performed on NAND flash memory reliably is known to be limited to 10,000 to 1,000,000.
FIG. 1 shows a diagram of the manner in which a block is re-written using current wear leveling techniques. During a write operation in which a block of information is previous written thereto and is now being re-written, which occurs readily when a host re-writes a file, the block 10, which is shown to include 128 pages with each page being 2024 bytes of data and 64 bytes of overhead or spare, is essentially moved to a different block, or a new block 14. Re-written information, which is shown to be included in the buffer memory controller 12 is written into a corresponding location of the new block 16 and the remaining information that is not being re-written of the block 10 is then moved to the block 16. The old block 18, which is essentially the block 10 is then erased. The problem with this technique is that each time there is a re-writing of a block, an erase operation needs to be performed thereby adversely affecting the life span of the memory cells within the flash memory.
Additionally, the life time of the MLC flash memory is limited to 10,000 erase cycles or operations. An entire block must be erased in MLC flash memory before a page can be re-programmed. Therefore, wear leveling techniques are needed to address the MLC flash re-programming problem.
Wear leveling is a technique used to distribute use of the memory cells within the MLC and/or SLC or any other type of non-volatile (or flash) memory evenly thereby extending the lifetime of the latter. In performing wear leveling, a memory controller is used to re-map logical addresses, used by a host to identify addresses into which information is to be written or read from, to different physical addresses, used by the memory controller to address the flash memory to store or read information from the host, so that write operations are evenly distributed among the memory cells thereby extending the endurance of the flash memory.
In light of the foregoing, there is a need for flash memory to have increased reliability.

Page and block management algorithm for NAND flash


The present invention involves a process for preparing a stable final formulation product of a compound of formula I,

The present invention relates to a process for preparing a stabilized form of antibiotic compounds, in particular a carbapenem antibiotic composition.
Betalactams, a broader class of antibiotics which is further defined as carbapenems are useful for the treatment of infectious diseases including gram positive and negative, and aerobic and anaerobic bacteria. Carbapenems were first isolated from fermentation media in 1974 and were found to have broad-spectrum antibacterial activity. Since this discovery substantial investigations have been made into new carbapenem derivatives and many hundreds of patents and scientific papers have been published. The commercially marketed carbapenem is imipenem (N-formimidoyl thienamycin), which has a broad range of antibacterial activity. This compound can be used in the treatment of any disease that is conventionally treated with antibiotics, for example in the treatment of bacterial infection in mammals including humans.
It has been reported that dimerization of carbapenem is inhibited via the formation of a reversible equilibrium adduct between carbon dioxide and monosodium salt of carbapenem compound as shown below, where Ka and Keq are equilibrium constants of the reactions.
During the manufacture of bulk antibiotic products such as carbapenem antibiotic, the pharmaceutical compound is prepared by chemical synthesis from raw materials in large quantities. Carbapenem antibiotic compounds are prepared in large batches as salt form, monosodium salt as shown above, which are weak crystalline solids, hygroscopic at ambient conditions, and unstable at room and refrigerated temperatures. Because the compound is unstable at a temperature above about xe2x88x9220xc2x0 C., the bulk compounds must be stored at a low temperature (about xe2x88x9220xc2x0 C.) to prevent degradation into dimers or open ring by-products. Although the unstable compound of carbapenem, after bulk manufacturing, can be stored for long periods of time at a low temperature, it must be converted into a stable formulation prior to use as once-a-day antimicrobial agent for intravenous (IV) or intramuscular (IM) administration.
Several reported cases for preparing carbapenem antibiotic compounds have shortcomings of teaching how to achieve a stable form of carbapenem antibiotics in its final formulation and manufacturing process. In particular, they fail to teach how to achieve the conversion of salt-containing carbapenem compound to a formulation exhibiting acceptable levels of degradates required for solid state and reconstitution stability for dosing to patients.
For example, Almarsson et al. (WO 98/18800) discloses a method for stabilizing carbapenem antibiotics by carboxylating the pyrrolidinyl amino acid with a carbon dioxide source, but fails to teach the steps necessary to obtain the stable form of carbapenem during its formulation process.
Zimmerman et al. (U.S. Pat. No. 5,952,323) relates a method of stabilizing a carbapenem compound by incorporating carbon dioxide source, but it also does not provide how to achieve the stabilized form of carbon dioxide adduct in its final composition.
In light of the above, an objective of the present invention is to provide a process for formulating a final product of stable antibiotic compound, in particular carbapenem antibiotic for the treatment of infectious diseases which include gram positive and negative, and aerobic and anaerobic bacteria. Another object of the present invention is to provide a novel manufacturing process to prepare the final formulation product of carbapenem antibiotic with acceptable levels of degradates, solid state stability and solution stability for dosing.
The present invention is directed to a process for preparing a final formulation product of a compound of Formula I,
or its pharmaceutically acceptable salt, hydrate or solvate wherein,
R1 is:
(a) 1-hydroxyethyl,
(b) 1-fluoroethyl, or
(c) hydroxymethyl;
R2 and R3 are independently:
(a) hydrogen, or
(b) (C1-C6)-alkyl;
R4, R5 and R6 are independently
(a) hydrogen
(b) (C1-C6)-alkyl, or
(c) alkali-metal or alkali earth-metal wherein the alkali-metal or alkali earth-metal is sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium; and
R7 and R8 are independently:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) (C1-C6)-alkyl,
(e) nitro,
(f) hydroxy,
(g) carboxy,
(h) (C1-C6)-alkoxy,
(i) (C1-C6)-alkoxycarbonyl,
(j) aminosulphonyl,
(k) (C1-C6)-alkylaminosulphonyl,
(l) di-(C1-C6)-alkylaminosulphonyl,
(m) carbamoyl,
(n) (C1-C6)-alkylcarbamoyl,
(o) di-(C1-C6)-alkylcarbamoyl,
(p) trifluoromethyl,
(q) sulphonic acid,
(r) amino,
(s) (C1-C6)-alkylamino,
(t) di-(C1-C6)-alkylmino,
(u) (C1-C6)-alkanoylamino,
(v) (C1-C6)-alkanoyl(N-(C1-C6)-alkyl)amino,
(w) (C1-C6)-alkanesulphonamido, or
(x) (C1-C6)-alkyl-S(O)n wherein n is 0-2;
comprising the steps of:
(1) charging a solution of carbon dioxide source having a pH range of about 6.0 to about 12.0 into a reaction vessel;
(2) adding an effective amount of a mole ratio of a base and an active ingredient into the reaction vessel containing the solution of carbon dioxide source to maintain pH at about 6.0 to about 9.0 and a temperature range of about xe2x88x923xc2x0 C. to about 15xc2x0 C.;
(3) lyophilizing the solution of Step (2) to yield the final formulation product of a compound of formula I with less than about 10% of moisture content.
The present invention relates to a process for preparing a stable form of carbapenem compound in its formulation and manufacturing processes. More specifically, the present invention involves a process for preparing a stabilized carbon dioxide adduct of carbapenem antibiotic by incorporating suitable carbon dioxide source to unstable salt form of carbapenem antibiotic, in particular monosodium salt of carbapenem, at suitable reaction conditions. The stable carbon dioxide adduct of the carbapenem antibiotic formulation is useful for the treatment of bacterial infections in mammal patients, which can be administered intravenously or intramuscularly.
The present invention is directed to a process for preparing a final formulation product of a compound of Formula I,
or its pharmaceutically acceptable salt, hydrate or solvate wherein,
R1 is:
(a) 1-hydroxyethyl,
(b) 1-fluoroethyl, or
(c) hydroxymethyl;
R2 and R3 are independently:
(a) hydrogen, or
(b) (C1-C6)-alkyl;
R4, R5, and R6 are independently
(a) hydrogen
(b) (C1-C6)-alkyl, or
(c) alkali-metal or alkali earth-metal wherein the alkali-metal or alkali earth-metal is sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium; and
R7 and R8 are independently:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) (C1-C6)-alkyl,
(e) nitro,
(f) hydroxy,
(g) carboxy,
(h) (C1-C6)-alkoxy,
(i) (C1-C6)-alkoxycarbonyl,
(j) aminosulphonyl,
(k) (C1-C6)-alkylaminosulphonyl,
(l) di-(C1-C6)-alkylaminosulphonyl,
(m) carbamoyl,
(n) (C1-C6)-alkylcarbamoyl,
(o) di-(C1-C6)-alkylcarbamoyl,
(p) trifluoromethyl,
(q) sulphonic acid,
(r) amino,
(s) (C1-C6)-alkylamino,
(t) di-(C1-C6)-alkylmino,
(u) (C1-C6)-alkanoylamino,
(v) (C1-C6)-alkanoyl(N-(C1-C6)-alkyl)amino,
(w) (C1-C6)-alkanesulphonamido, or
(x) (C1-C6)-alkyl-S(O)n wherein n is 0-2;
comprising the steps of:
(1) charging a solution of carbon dioxide source having a pH range of about 6.0 to about 12.0 into a reaction vessel;
(2) adding an effective amount of a mole ratio of a base and an active ingredient into the reaction vessel containing the solution of carbon dioxide source to maintain pH at about 6.0 to about 9.0 and a temperature range of about xe2x88x923xc2x0 C. to about 15xc2x0 C.;
(3) lyophilizing the solution of Step (2) to yield the final formulation product of a compound of formula I with less than about 10% of moisture content.
A preferred embodiment of the present invention is a process for preparing a formulation of a compound of Formula Ia,
or its pharmaceutically acceptable salt, hydrates or solvate wherein,
R4, R5, and R6 are independently:
(a) hydrogen
(b) (C1-C6)-alkyl, or
(c) alkali-metal or alkali earth-metal wherein the alkali-metal or alkali earth-metal is sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium;
comprising the steps of:
(1) charging a solution of carbon dioxide source having a pH range of about 6.0 to about 12.0 into a reaction vessel;
(2) adding an effective amount of a mole ratio of a base and an active ingredient into the reaction vessel containing the solution of carbon dioxide source to maintain pH at about 6.0 to about 9.0 and a temperature range of about xe2x88x923xc2x0 C. to about 15xc2x0 C.;
(3) lyophilizing the solution of Step (2) to yield the final formulation product of a compound of formula I with less than about 10% of moisture content.
An aspect of the process as recited above is where the carbon dioxide source is selected from the group consisting of carbon dioxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, magnesium carbonate, lithium carbonate, and a mixture thereof. The preferred carbon dioxide source is sodium bicarbonate.
Another aspect of the process recited above is where the carbon dioxide source in Step (1) is present in an amount relative to the amount of active ingredient, wherein a mole ratio of carbon dioxide source to the active ingredient is about 0.5 to about 1.5, preferably about 0.8 to about 1.2.
Yet another aspect of the process as recited above is where the pH range in Step (1) is about 7.0 to about 9.0.
Still another aspect of the process as recited above is where a temperature range in Step (1) is about xe2x88x923xc2x0 C. to about 15xc2x0 C.
Still another aspect of the process as recited above is where the active ingredient is a compound of formula (a),
wherein R1, R2, R3, R4, R7 and R8 are as defined above.
Still another aspect of the process as recited above is where the preferred active ingredient is a compound of formula (a)xe2x80x2
Another aspect of the process as recited above is where the base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide.
Yet another aspect of the process as recited above is where the base is sodium hydroxide at a concentration range of about 1N to about 3N.
Still another aspect of the process as recited above is where the effective amount of a mole ratio of a base to an active ingredient in Step (2) is about 0.7 to about 1.0.
Still another aspect of the process as recited above is where the mole ratio of a base to an active ingredient in Step (2) is about 0.8 to about 0.9.
Still another aspect of the process as recited above is where the pH range in Step (2) is about 7.0 to about 8.0.
Still another aspect of the process as recited above is where the temperature range in Step (2) is about xe2x88x921xc2x0 C. to about 5xc2x0 C.
Still another aspect of the process as recited above is where the base is added followed by the addition of the active ingredient in Step (2).
Still another aspect of the process as recited above is where the temperature range in Step (2) is about xe2x88x921xc2x0 C. to about 5xc2x0 C.
Still another aspect of the process as recited above is where the Step (2) further comprises a titration of the solution using a titrating agent to maintain the pH of the solution at a range of about 6.5 to about 8.5.
Still another aspect of the process as recited above is where the titrating agent is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, calcium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide.
Still another aspect of the process as recited above is where the moisture content of the final formulation product is less than about 5%.
Still another aspect of the process as recited above is where the step (3) initially further comprises the following steps of:
(a) filtering the final formulation product into a receiving vessel using a sterilizing filter;
(b) aseptically filling the filtered final formulation product into a sterile vial; and
(c) placing a lyophilization stopper on the filled sterile vial containing the final formulation product.
It is further understood that the substituents recited above would include the definitions recited below, and unless otherwise stated or indicated, the definitions shall apply throughout the specification and claims.
As used herein, the term xe2x80x9calkylxe2x80x9d includes those alkyls of a designated number of carbon atoms of either a straight, branched or cyclic configuration. Examples of xe2x80x9calkylxe2x80x9d includes but are not limited to: methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, and the like.
The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and the like.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refer to fluorine, chlorine, bromine and iodine.
As used herein, the term xe2x80x9c1 mole equivalentxe2x80x9d is defined as 1 mole of carbon dioxide source per 1 mole of active ingredient (or active drug), wherein carbon dioxide source includes carbon dioxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, magnesium carbonate, lithium carbonate, and a mixture thereof.
The term xe2x80x9cactive ingredient,xe2x80x9d also refers to as xe2x80x9cbulk drug,xe2x80x9d xe2x80x9cbulk active drug,xe2x80x9d xe2x80x9cbulk active beta-lactamxe2x80x9d or xe2x80x9cbulk active carbapenem,xe2x80x9d refers to the amount of actual unstable, beta-lactam, carbapenem and/or alkali-metal salt or alkali earth-metal salt containing carbapenem removed from cold storage. The preferred active ingredient is a compound of formula of (a),
wherein
R1 is:
(a) 1-hydroxyethyl,
(b) 1-fluoroethyl, or
(c) hydroxymethyl;
R2 and R3 are independently:
(a) hydrogen, or
(b) (C1-C6)-alkyl;
R4, R5, and R6 are independently
(a) hydrogen
(b) (C1-C6)-alkyl, or
(c) alkali-metal or alkali earth-metal wherein the alkali-metal or alkali earth-metal is sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium; and
R7 and R8 are independently:
(a) hydrogen,
(b) halo,
(c) cyano,
(d) (C1-C6)-alkyl,
(e) nitro,
(f) hydroxy,
(g) carboxy,
(h) (C1-C6)-alkoxy,
(i) (C1-C6)-alkoxycarbonyl,
(j) aminosulphonyl,
(k) (C1-C6)-alkylaminosulphonyl,
(l) di-(C1-C6)-alkylaminosulphonyl,
(m) carbamoyl,
(n) (C1-C6)-alkylcarbamoyl,
(o) di-(C1-C6)-alkylcarbamoyl,
(p) trifluoromethyl,
(q) sulphonic acid,
(r) amino,
(s) (C1-C6)-alkylamino,
(t) di-(C1-C6)-alkylmino,
(u) (C1-C6)-alkanoylamino,
(v) (C1-C6)-alkanoyl(N-(C1-C6)-alkyl)amino,
(w) (C1-C6)-alkanesulphonamido, or
(x) (C1-C6)-alkyl-S(O)n wherein n is 0-2;
The most preferred active ingredient is a compound of formula of (a)xe2x80x2,
The term xe2x80x9cactive drug,xe2x80x9d as used herein, is defined as the actual amount of beta-lactam, unstabilized and stabilized carbapenem, and alkali metal salt-containing carbapenem and carbon dioxide-containing carbapenem.
The term xe2x80x9cquantum sufficitxe2x80x9d (xe2x80x9cq.s.xe2x80x9d), as used herein, is defined as the amount of a reagent necessary to increase the batch weight or volume to a specified total. As an example, a q.s. of 95% by wt % means the amount of reagent required to bring the weight percent up to 95% by weight based on 100% total weight.
The term xe2x80x9csolid state stabilityxe2x80x9d is defined as the ability of finished solid and lyophilized formulation (a porous off-white cake) at the end of about 2 years to deliver the prescribed and labeled dosage of active drug.
The term xe2x80x9creconstitution stabilityxe2x80x9d is defined as the ability of a solution prepared by the finished solid and lyophilized formulation into an appropriate diluent (i.e. 0.9% saline for injection, 1% Lidocaine, and etc.) to deliver the prescribed and labeled dosage of active drug.
The batch-wise process of the present invention is carried out under aseptic conditions and requires several reagents and processing units to prepare formulations of high pharmaceutical quality. The present process provide a high rate conversion from the alkali metal salt, such as monosodium salt of carbapenem to the carbon dioxide adduct and the low by-product formation, such as dimers and open ring compounds. The reaction parameters and conditions such as the mole ratio of carbon dioxide source and active ingredient, mole ratio of base and active ingredient (active bulk carbapenem), reaction temperatures, pH of the solution, proper mixing, and appropriate lyophilization parameters are critical to obtain a final formulation product of high pharmaceutical quality.
The process for preparing a stable intravenous formulation of a carbon dioxide adduct of a carbapenem requires the processing temperature of about xe2x88x923xc2x0 C. to about 15xc2x0 C., preferably about xe2x88x921xc2x0 C. to about 5xc2x0 C., and the pH of the pre-lyophilized active solution to be about 6.0 to about 12.0, preferably about 7.0 to about 9.0. The process is carried out under aseptic conditions. All reagents used during the present processes meet United States Pharmacopeia and National Formulary standards unless otherwise stated.
Methods of preparing the compound of the present invention are illustrated in the following process and examples. They are provided for illustrative purposes and should not be construed as limiting the invention disclosed herein.
PROCESS
Sodium hydroxide solution of about 1N to about 3N is prepared by dissolving a sufficient amount of sodium hydroxide NF pellets in a sufficient amount of Water For Injection (WFI). While adding the sodium hydroxide, the solution is constantly mixed to ensure complete dissolution. The compounder/reactor (200L stainless steel jacketed vessel) is jacketed and cooled to maintain at a low temperature to prevent bulk drug degradation during the process. A variable agitation system is attached to the compounder/reactor to ensure complete dissolution of the bulk drug into solution. Generally, about 40% by weight or 60% by volume of WFI is charged into the compounder/ reactor to begin the process, and the water is cooled to the temperature range of about xe2x88x923xc2x0 C. to about 15xc2x0 C., preferably about xe2x88x921xc2x0 C. to about 5xc2x0 C. To measure the pH of the solution in the compounder/reactor, appropriate pH and temperature devices are used. The pH meter is typically calibrated with buffer solution of pH 7.0 and 10.0. To maintain the pH of the solution within the required range during the batch-wise process, an appropriate pH controller system equipped with a pump is utilized to meter sodium hydroxide solution into the compounder/reactor.
After the WFI in the compounder/reactor is cooled, mixing is commenced to prevent localization of pH, temperature, and concentration of reagents and bulk antibiotic drug. A sufficient amount of carbon dioxide source such as sodium bicarbonate and/or sodium carbonate is added to the compounder/reactor under continuous mixing of the WFI to provide a final formulation concentration of about one mole equivalent (a mole ratio of carbon dioxide source to the active ingredient is about 0.5 to about 1.5, preferably about 0.8 to about 1.2). The solution is mixed until the carbon dioxide source, such as carbonates are completely dissolved. The pH of the solution is measured to ensure that it is about 6.0 to about 12.0, preferably about 7.0 to about 9.0 at a temperature range of about xe2x88x923xc2x0 C. to about 15xc2x0 C. It is preferred that the temperature and pH of the solution be confirmed prior to beginning the addition of bulk drug. The unstable bulk carbapenem drug is removed from a refrigerated unit held at about xe2x88x9220xc2x0 C. or lower and may be thawed to a temperature of from about 5xc2x0 C. to about 25xc2x0 C. for about 1 hour. A sufficient amount of the bulk drug is weighted out to provide a final formulation concentration of carbapenem to be about 200 g of active drug (as free acid)/liter formulation.
During the addition of the bulk active carbapenem to the compounder/reactor, the carbonate solution is constantly mixed. Generally, the mixing begins at lower agitation speed during the initial addition of bulk drug to the solution and as the amount of bulk in the solution is increased, mixing may be increased proportionally thereto. The primary purpose of mixing is to ensure complete dissolution of the bulk drug into the solution. As necessary, sodium hydroxide solution is added to the compounder/reactor during the addition of the bulk drug to maintain the pH of the solution to be about 6.0 to about 9.0, preferably about 7.0 to about 8.0. The bulk drug is generally slowly added to the compounder/reactor at a constant rate for about 30 minutes to about 90 minutes to enhance dissolution. At the end of the bulk drug addition, the solution is mixed for additional few minutes to ensure complete dissolution. The q.s. of the batch weight is adjusted to about 95% by weight of the final weight of the formulation with WFI, if needed, while maintaining the temperature at about xe2x88x921xc2x0 C. and about 5xc2x0 C. Further titration using sodium hydroxide may be performed over a 10 minute to 20 minute period to ensure a mole ratio of base (NaOH) and bulk active drug to be in the range of from about 0.7 to about 1.0, preferably about 0.8 to about 0.9. Finally, the batch is adjusted to 100% by weight of its final weight with WFI with moderate mixing.
Afterwards, the solution is filtered through a sterilizing filter such as that from about 0.2 xcexcm to about 0.25 xcexcm. When making larger batches, generally from about 10L to about 200L in a compounder/rector, the compounding vessel is sealed and pressurized to initiate filtration. Filtration can be done either by pumping the solution through sterilizing filters with an appropriate pump in the absence of compounding vessel that can be pressurized or appropriate gas to carry out filtration by pressure. The receiving vessel should be sterile and cooled to a temperature range of about xe2x88x923xc2x0 C. to about 15xc2x0 C. The density of the filtered formulation solution is generally about 1.0 g/mL to about 1.2 g/mL at about 0xc2x0 C. to about 5xc2x0 C., typically about 1.1 g/mL. Lyophilization of the completed formulation is preferred to simplified manufacture. However, the solution could be bulk lyophilized and the resulting powder filled into packages for use. If the processed by lyophilization in vials, the filtered formulation can be filled into vials and partially sealed with dry sterile siliconized lyophilization stoppers. In the following examples conventional 20 mL vials and 15 mL ADD-Vantage(trademark) vials are utilized. The vials are filled at specified target fill and then placed onto lyophilizer shelves, which are pre-cooled to a temperature of about xe2x88x9240xc2x0 C. to about xe2x88x9245xc2x0 C., typically about xe2x88x9240xc2x0 C. Suitable lyophilization cycle is then run with vials.
The lyophilization cycles used herein for the different vials are described in the examples below. Generally, the cycle requires the vials to be soaked at about xe2x88x9240xc2x0 C. for about two hours and then heated to a temperature range of about xe2x88x9225xc2x0 C. to about xe2x88x9215xc2x0 C. shelf temperature at a rate of about 0.5xc2x0 C./minute. The temperature is normally maintained at about xe2x88x9225xc2x0 C. to about xe2x88x9215xc2x0 C., and the pressure of the lyophilizer chamber is maintained at about 80 mTorr for about 48 hours to about 60 hours. The vials are heated to about 10xc2x0 C. shelf temperature at a rate of about 0.1xc2x0 C./minute and then to about 40xc2x0 C. shelf temperature at a rate of about 0.5xc2x0 C./minute, and maintained at 40xc2x0 C. for up to about three hours at a pressure of about 80 mTorr or lower. The vials are then heated to about 60xc2x0 C. shelf temperature at a rate of about 0.5xc2x0 C./minute and held there at about 80 mTorr or less for about 3 hours to about 10 hours. The shelves are then cooled to ambient temperature (about 20xc2x0 C.-30xc2x0 C.). The vials are completely sealed under a partial vacuum of about 0.9 bar/700 Torr or lower before removing them from the lyophilizer. The vials are stored at a temperature not exceeding about 25xc2x0 C. until needed.

Process for formulation of antibiotic compounds

Abstract: or its pharmaceutically acceptable salt, hydrate or solvate by incorporating a suitable carbon dioxide source to an unstable monosodium adduct of carbapenem antibiotic compound.


Provided is a simulation method performed by a process simulator, implemented with a recurrent neural network (RNN) including a plurality of process emulation cells, which are arranged in time series and configured to train and predict, based on a final target profile, a profile of each process step included in a semiconductor manufacturing process. The simulation method includes: receiving, at a first process emulation cell, a previous output profile provided at a previous process step, a target profile and process condition information of a current process step; and generating, at the first process emulation cell, a current output profile corresponding to the current process step, based on the target profile, the process condition information, and prior knowledge information, the prior knowledge information defining a time series causal relationship between the previous process step and the current process step.

Example embodiments disclosed herein relate to a simulation device for a semiconductor device, and more particularly, relate to a simulation system for simulating a process of manufacturing a semiconductor device and a simulation method thereof.
A machine learning technique used in various technical fields may improve performance and efficiency in performing a task. The machine learning technique may be applied to tune a semiconductor process, to reduce costs and provide high accuracy.
In designing the semiconductor process, a fine tuning of a process is needed to obtain an optimum profile for equipment or conditions to be applied to each process step. To tune a specific process (e.g., an etching process) including a plurality of steps (or process steps), a plurality of profiles corresponding to the plurality of steps are required. However, there is a limitation in checking the plurality of profiles to be applied to the respective plurality of process steps due to cost and technology limitations.
In general, a process simulation may be used to obtain a profile of a completed process. However, only a final profile is obtained through the process simulation, and a profile associated with an intermediate step of a specific process may not be obtained. Accordingly, it is difficult to trace faults and problematic process steps of a process.

Simulation system for semiconductor process and simulation method thereof