text:
A general purpose programmable neural computer which parallel processes analog data. The neural computer comprises neural elements for outputting an analog signal in response to at least one input signal, synaptic circuits interfaced with the neural elements for modifying gains of the neural elements, and switching circuits interfaced with the synaptic circuits and the neural circuits for routing signals between the synapse circuits and the neural circuits and for modifying the synaptic time constants, thereby changing connection architecture of the general purpose analog computer as desired. In this manner, the neural computer of the invention can be programmed to learn different confirurations as well as different synaptic values.
1. A general purpose neural computer comprising:
electronic neuron modules for outputting an analog output signal in accordance with at least one analog input value received on respective inputs thereof;
modifiable synapse modules interconnected via interconnections with said electronic neuron modules for modifying synaptic weights of said at least one analog input value in accordance with first configuration signals;
switching modules for routing second configuration signals between each respective electronic neuron module and synapse module so as to change said interconnections between said electronic neuron modules and synapse modules; and
a processor for providing said first configuration signals to said synapse modules for modifying synaptic weights associated with said synapse modules and said second configuration signals to said switching modules for reconnecting said electronic neuron modules and synapse modules in accordance with a desired neural computing architecture.
2. A neural computer as claimed in claim 1, wherein each electronic neuron module comprises an output line for outputting said analog output signal, electronic neurons for outputting an analog signal of at least a minimum level when an analog input signal thereto is above a predetermined input threshold, and an analog multiplexer responsive to output analog signals output by each of said electronic neurons for sequentially connecting said output analog signals to said output line.
3. A neural computer as in claim 2, wherein said analog multiplexer comprises a shift register for sequentially shifting said output analog signals to said output line.
4. A neural computer as in claim 2, wherein each of said electronic neurons comprises a first current source for controlling said minimum level at said predetermined input threshold, differential amplifying means responsive to said first current source for varying said predetermined input threshold, and a second current source responsive to said differential amplifying means for establishing an externally adjustable threshold bias.
5. A neural computer as in claim 1, wherein each modifiable synapse module comprises a plurality of synapses and means associated with each of said synapses for storing said first configuration signals from said processing means as synaptic weights associated with each corresponding synapse.
6. A neural computer as in claim 5, wherein each of said switching modules comprises an array of analog switches for connecting each respective electronic neuron module to said synapse modules as specified by said second configuration signals and means for controlling time constants of transfer functions of said synapses.
7. A neural computer as in claim 6, wherein said time constants controlling means comprises a plurality of low pass filters for low pass filtering a transfer function of an associated synapse, each low pass filter having an adjustable resistance and capacitance.
8. A general purpose neural computer comprising:
electronic neurons for outputting an analog output signal in accordance with at least one analog input value received on respective inputs thereof;
modifiable synapses responsive to respective outputs of said electronic neurons for modifying synaptic weights of said at least one analog input value in accordance with input configuration signals;
adjustable low pass filters having a variable capacitor and a variable resistor for low pass filtering a transfer function of an associated synapse so as to control time constants of said associated synapse;
a processor for providing said configuration signals to said synapses for modifying synaptic weights associated with said synapses and to said low pass filters for modifying values of said variable capacitor and resistor so as to vary said time constants of said associated synapse; and
summing amplifiers for summing outputs of said low pass filters and providing a sum value to respective ones of said electronic neurons as said at least one analog input value.
This application is a continuation-in-part of application Ser. No. 428,455, filed on Oct. 30, 1989, now abandoned, which is a continuation of application Ser. No. 128,321, filed on Dec. 3, 1987, now abandoned.
This invention relates to analog processing of data. More specifically, this invention relates to the implementation of an artificial neural network which is useful for learning an environment and for analog processing of analog signals inputs to the neural network.
Pattern recognition has been accomplished in various ways in the prior art. One of the best known methods of pattern recognition is typified by a simple radar system wherein a beam of electromagnetic energy illuminates a target and is backscattered to a receiver set which is coupled to a computer that analyzes the back-scattered signal and forms an image of the target. Similarly, sonar systems accomplish the same result with acoustical type signals.
Regardless of the transmission and receiving apparatus used in these systems, a multi-purpose, digital computer is continually utilized to perform complex calculations to obtain an output which identifies the input signal. The types of computers used in the prior art to perform such calculations have been exclusively sequential machines that require sophisticated programming to effectively perform pattern recognition algorithms such as Fourier transforms, fast Fourier transforms and similar types of algorithms known to those with ordinary skill in the art.
A major drawback which exists with the use of digital, sequential computers in pattern recognition systems is the inherent limitation of these computers to perform their function only in a strictly sequential fashion. It is known that sequential, digital computers perform one step of a process or algorithm over each machine cycle. In this manner, successive iterations are repeated over a large number of computer machine cycles of a complex algorithm in order to perform pattern recognition and other computer functions.
Depending upon the complexity of the algorithm, the digital computer must perform enormous numbers of machine cycles to form the complete solution of a complex algorithm. For example, when higher order differential equations must be solved simultaneously or when a large number of differential equations must be solved either simultaneously or sequentially, the number of machine cycles required to solve the equations increases drastically. With these drastic increases in machine cycles comes an increased time period for the digital, sequential computer to perform a complete analysis of incoming data. Those skilled in the art will appreciate that complete and useful pattern recognition with such digital computers can take hours or even days. Thus, the use of digital computers generally does not allow pattern recognition in "real-time."
There is therefore a long-felt need in the computer art for a machine which can drastically reduce the time required to perform algorithmic tasks and to provide methods and systems for fast and efficient pattern recognition. Some form of parallel processing of incoming signals could perform this function, also, the use of a parallel processor or a machine capable of inherent parallelism could allow pattern recognition of a complex signal in real-time.
An additional problem which has existed in the computer and pattern recognition arts arises from the requirement that signals be resolved into digital components before they may be processed by a sequential, digital computer. This requires that all incoming signals be first "digitized" by an "analog to digital" component of the pattern recognition system before the digital computer can begin processing the signal with its particular pattern recognition algorithm. This places many burdens on prior art pattern recognition systems in that it requires expensive hardware to implement analog to digital conversion and increases the overall processing time of such systems by requiring the analog to digital conversion step. Thus, a pattern recognition system which utilizes incoming analog signals directly without analog to digital conversion is highly desirable. Such a system has not been known heretofore in the art, however.
Additionally, it is highly desirable to utilize systems for pattern recognition that employ parallel processing of analog signals. Such systems also have not been known in the pattern recognition art. Thus, there is a continuing need for a computer system which utilizes analog signals and performs parallel processing. This need requires an effective system to achieve fast, parallel processing of analog signals.
Apparatus have been developed which simulate or approximate certain aspects of the behavior of neural networks. An example of such a system is embodied in U.S. Pat. No. 4,773,024 to Faggin et al., which discloses a recognize-only embodiment of a recognition matrix having contacts comprised of a forward matrix and a reverse matrix. The contacts disclosed in Faggin et al. are permanently programmed by the user for a class of events and are therefore static. The user typically performs a learning function on a computer for all the events which the system will be programmed to recognize. The pattern of convergence responses and contact structure characteristics which cause convergence responses for the class of events as a whole are then examined and optimized for maximum recognition power and minimal confusion. This pattern of convergence responses is permanently programmed in the contacts of the program reverse matrices.
A similar system is disclosed in U.S. Pat. No. 4,774,667 to Buckley, wherein self-organizing circuits connected to receive a plurality of input signals representing constituent elements of input information are taught. The self-organizing circuits disclosed in Buckley are operable to effect identification of the pattern of constituent elements by combining the influence that each constituent element has on the pattern of constituent elements. A mechanism is provided to modify the influence which each constituent element has on the signal pattern of constituent elements based upon cumulative Boolean functions between the input signals to each circuit output. Furthermore, a mechanism connected to vary the influences based upon competition among the input signals is provided by Buckley in col. 6, line 9 through col. 9, line 2 thereof.
In addition, electronic circuits which mimic neural networks and associative memories are taught in U.S. Pat. No. 4,660,166 to Hopfield, wherein the use of amplifiers connected to a matrix of input and output conductors to produce stored outputs in response to input signals is disclosed. Each connection is implemented with a network of resistors connected to the inputs and outputs in the amplifiers. The resistive values are selected to satisfy the circuit's "equation of motion." The network disclosed in the Hopfield patent is driven to a stable state at the complementary output of the amplifiers which provide an output code word that approximates the problem's solution as described in Hopfield, col. 6, line 10 through col. 10, line 7 thereof.
The aforementioned patents do not solve a long-felt need in the art for methods and apparatus which can drastically reduce the time required to achieve analog processing of data and pattern recognition. While the aforementioned patents provide a modicum of parallel processing, they generally either rely partially on standard digital computers for their data processing capabilities or do not themselves provide pattern recognition but merely pre-process analog data for ultimate conversion to digital signals and subsequent digital processing.
One of the inventors of the subject matter herein claimed and disclosed published a paper which theoretically defined neuron behavior and modelled artificial neurons comprising electronic components based on the input-output relationships of real brain neurons. See. P. Mueller, T. Martin and F. Putzrath, "General Principals of Operations in Neuron Nets with Application to Acoustical Pattern Recognition," reprinted in Biological Prototypes and Synthetic Systems, Vol. 1, p. 192-212 (1962). In the aforementioned paper, a neuron's behavior as a logic device was disclosed. As described therein, the neuron has both excitatory and inhibitory inputs and excitatory and inhibitory feedback which cause the neuron to fire when the combination of these inputs exceeds a threshold voltage. Because firing neurons can be observed without outputting a uniform voltage, Boolean algebra was disclosed to be useful as a tool for quantitative treatment of the relationship between the input and the output of the neuron. Additionally, examples of electronic neurons which simulate the behavior of brain neurons were described in this paper.
As noted in the above-mentioned paper, general electronic neurons may approximate the basic properties of biological neurons. One of inventors of the subject matter herein claimed and disclosed has also recognized that artificial neurons so constructed would be particularly useful in artificial neural networks for speech recognition. See P. Mueller, "Principles of Temporal Pattern Recognition in Artificial Neuron Nets with Application in Speech Recognition," reprinted in Artificial Intelligence. IEEE, pp. 138-44 (1963).
While the general properties of artificial neurons modelled after brain neurons has thus been known in the art at least since the early 1960s, there remains a long-felt need in the art for artificial neural networks which function as general purpose neural computers. None of the aforementioned patents or papers disclose systems which solve a long-felt need in the art for electronic artificial neural networks that process data in analog form, thereby providing pattern recognition and general purpose neural computing.
General purpose analog computers comprising artificial neural networks provided in accordance with the present invention solve a long-felt need in the art for analog processing of data. This analog processing of data is much more rapid and efficient than the standard digital serial processing of data which has heretofore been used and eliminates the need to digitize analog signals before processing. General purpose analog computers claimed and disclosed herein also enjoy the advantage of being programmable and are thus self-modifiable to perform a variety of analog computational tasks. Furthermore, the analog circuits described herein are preferably modular and therefore neural computers which utilize them are arbitrarily expandable to be made as powerful as necessary for a given computational task.
In accordance with the present invention, analog neural modules which output analog signals in response to at least one analog input signal comprise a plurality of artificial neural elements wherein each of the neural elements outputs analog signals when analog input signals to the neural elements are above an input threshold, the neural elements having a minimum output threshold, a plurality of input lines connected to the plurality of artificial neural elements for interfacing the analog neural module with its environment, and analog multiplexing means interfaced with the plurality of neural elements for combining the analog output signals of the plurality of artificial neural elements.
Further in accordance with the present invention, methods of processing analog data are provided comprising the steps of inputting analog signals to an artificial neural network comprising a plurality of artificial neural elements, setting a synaptic memory with weights that scale analog outputs from the neural elements according to the weights, multiplexing the analog outputs from the neural elements to obtain a common analog output for the artificial neural network, switching the weighted analog outputs between at least one other subsequent artificial neural network, thereby changing connection architecture between the artificial neural networks each having a common analog output, and monitoring the common analog outputs from the artificial neural networks.
FIG. 1 is a block diagram of a general purpose neural computer provided in accordance with the present invention.
FIG. 2A is an analog neural module provided in accordance with the present invention.
FIG. 2B illustrates graphs of the output of the analog neural modules of FIG. 2A against weighted inputs.
FIG. 3 is an analog multiplexer used for multiplexing data from neural elements.
FIG. 4 is a preferred embodiment of a neural element having a minimum output at threshold.
FIG. 5 is a synaptic module used in neural networks provided in accordance with the present invention.
FIGS. 6A and 6B are graphs illustrating the linear output of synaptic weights as a function of input voltage.
FIG. 7 illustrates a digitized synaptic transfer function.
FIG. 8 is a switching module used in neural networks provided in accordance with the present invention.
FIG. 9A illustrates a simplified block diagram of a neural network provided in accordance with the present invention, while FIG. 9B illustrates the output of the neural network of FIG. 9A when a triangle wave is input.
FIG. 10 is an electrical circuit diagram illustrating another embodiment of a neural module provided in accordance with the present invention.
FIG. 11A illustrates a switching fabric for providing modifiable synaptic time constants in accordance with the present invention.
FIG. 11B illustrates a circuit for modifying the synaptic weights in a neural network in accordance with the invention.
Referring now to the drawings wherein like reference numerals refer to like elements, FIG. 1 shows a general purpose neural computer at 10 provided in accordance with the present invention. Neural computers provided in accordance with the present invention are loosely based on the cerebral cortex in the sense that there are separate neurons, axons, and synapses so that each neuron receives only a limited number of inputs. With such artificial neural computers, as contrasted to biological systems, the connections can be modified by an external control permitting exploration of different architectures with the additional adjustment of synaptic weights and neuron parameters. In accordance with the invention, the modification of the synaptic weights is generally controlled by a host computer 20 which is preferably a standard digital electronic computer.
In preferred embodiments, the electronic neural computer 10 comprises a plurality of each of the following elements. Artificial neurons (hereinafter referred to as "neurons") denoted at "N" are shown generally at 30. Synapses "SY" shown generally at 40 are interfaced with the neurons and other elements. Additionally, routing switches "SW" shown at 50 and connection lines "L" shown generally at 60 are provided. Host computer 20 is interfaced to the neural computer 10 through a plurality of interface lines 70 interfaced with the switch elements.
Arrays of neurons 30, synapses 40, switches 50 and lines 60 may be fabricated on VLSI chips for mounting on a plane or chip carrier to form separate modules. Modules may then be interconnected to form large general purpose neural computers. Neuron arrays are arranged in rows and columns and are surrounded by the synaptic and axon arrays.
Neural computers provided in accordance with the present invention process analog signals for real-world, real-time computations such as analyses of visual or acoustical patterns, robotics, and for the development of special purpose neural nets. While the neural computer 10 can itself run in a completely analog mode, connection architecture, synaptic gains and time constants, as well as neuron parameters are set digitally by host computer 20. For the determination of synaptic gains and the implementation of learning algorithms, neuron outputs also may be multiplexed, analog to digitally converted, and stored in a digital memory in host computer 20. It is expected that even a moderately sized computer of 103 to 105 neurons will achieve computational speeds that will exceed any current digital electronic computer.
FIG. 2A illustrates a neuron module 30 provided in accordance with the present invention. In preferred embodiments, the neuron module chip 30 contains neurons shown generally at 90. In yet further preferred embodiments and as an example of a neuron module 30 provided in accordance with the present invention, there are sixteen neurons 90 on neuron module (chip) 30. An analog multiplexer 100 is also provided which comprises a common output line 30 (OM) 110 which is connected to the host processor. The neuron module 30 has sixteen inputs (SIL1) shown generally at 120 both at the left and the right hand side in order to double the fan-in for the module. The input signals SILi are provided by the neighboring synaptic modules in the memory module's environment and in the neuron module's environment as will be determined below.
Each neuron 90 has a second input that sets the minimum output at threshold for the neurons 90 and which is common for all neurons 90 on the same chip. Threshold is set from one of the synapses which is connected to a fixed voltage. There are sixteen output lines (NOj) shown generally at 130 at the top and bottom of neuron module 30 which come from the sixteen neurons 90.
In further preferred embodiments, analog multiplexer 100 consists of sixteen analog switches which connect the neuron 90 output sequentially to the common output line 110. This output is buffered in by the signal, OM, that is sent to an analog to digital converter over the common line. The output signals are stored in the memory of the host computer 20. The multiplexer switches are, addressed in series by complementary clock signals CK. In yet further preferred embodiments, the addressing circuit is a 16-bit chip register that shifts a "1" from the input to the output. The shift register (not shown) is clocked by two phase clocks which are generated on-chip from a master clock, CK, coming from the host computer 20. In still further preferred embodiments, clock CK runs at about 2 MHz.
After the last neuron 90 has been read, a pulse, ORO, is sent to the ORI input of the next neuron module 30. After this occurs, the module sends its sixteen analog neuron outputs NOi sequentially through output line OM and then sends an ORO pulse to the next chip in a row of neuron modules 30. Thus, all neurons 90 are read out in sequence. After all the neuron modules 30 have been read, the host computer 20 sends an ORI pulse to the first neuron, N1, and the procedure repeats. In this fashion, all the neurons 90 on a board can be read out in a few milliseconds which is fast enough to record a series of snapshots of the state of the network.
Preferably, in order to synchronize the multiplexer 100 with the host computer 20 and the analog to digital converter, control line PH12 shown, generally at 140 between the neuron module 30 and host computer 20 sends a synchronizing signal generated by the host computer 20 to the memory module. Control line PHI2 140 also provides a control signal from host computer 20 which enables and disables analog multiplexer 100 in order to allow neurons 90 to be read in sequential fashion.
FIG. 2B illustrates the input and output relations of the neurons 90 as preferably idealized versions of typical biological neurons. The graphs in FIG. 2B illustrate the transfer function for each of the neurons 90. On the y axes, the output of the neurons (Eo) are shown, while the x axes illustrate the weighted sum of the inputs to each of the individual neurons. The neurons have an adjustable threshold, Vt, a linear transfer region above the threshold, an adjustable minimum output at threshold Ex, and a maximum output, Emax. For a fixed Vt and varying minimum outputs of threshold Ex from 0 to 1, the output of the neurons are linear to Emax. Similarly, for varying Vt 's the outputs of the neurons are linear to Emax. The graphs of FIG. 2B illustrate the linear nature of the output of the neurons 90 provided in accordance with the present invention as having minimum outputs at adjustable thresholds.
FIG. 3 illustrates the basic architecture of the analog multiplexer 100. As shown, shift register 150 is interfaced with each of the output lines 130 and common line OM at 110. The CK (clock), PHI2 and OR1 signals are input to shift register 150 while the ORO signal is an output of shift register 150. Shift register 150 may comprise a standard shift register readily available in the industry and is preferably a 16-bit shift register.
FIG. 4 illustrates a neuron circuit 90 provided in accordance with the present invention. Neuron circuit has a linear transfer region above the threshold, an adjustable minimum output as described with respect to FIG. 2B, and a maximum output. While the circuit of FIG. 4 is exemplary, other circuits may be designed which could give similar parametric values. The minimum output at threshold is controlled by current source 160. Current I, shown at 170 provides an externally adjustable threshold in the memory while controlling the output of differential amplifier 180 and the output of differential amplifier 190, although the output of differential amplifier 190 is significantly different since there is a voltage drop across resistor 200 which forms an input signal to differential amplifier 190. A further voltage drop across resistor 210 controls the output to differential amplifier 220. The output for the neuron circuit 90 is shown generally at 230 and is preferably a continuous voltage output. However, the voltage output could be in the form of voltage spikes or pulses when desired for a particular application.
In preferred embodiments, neuron 90 may be fabricated on a CMOS semiconducting chip. In still further preferred embodiments, the operation of the neuron 90 is in the current summing mode, and the output 230 is from about 0 to 4 volts. Preferably, a linear transfer function as illustrated in FIG. 2B is obtained with synaptic memory provided in accordance with the present invention. However, it will be recognized by those with skill in the art that a sigmoidal transfer function may also be obtained. It is further preferable to keep the output impedance of the neuron circuit 90 to less than about 1 KOhm and having a gain bandwidth product of about 900 KHz. Furthermore, the threshold adjustment could be logarithmic, positive or negative with a 5-bit resolution, and the adjustment of the minimum output at threshold may be between 0 to 4 volts with a 5-bit resolution. Multiple inputs can be provided to neuron circuit 90, although only one input is illustrated in FIG. 4, since in general multiple fan-in inputs are contemplated for neurons 90 provided in accordance with the present invention.
The threshold of each neuron is individually adjustable from the synapse Sy through an extra synapse that is connected to a fixed input voltage. In this way the threshold can be biased in either direction. A neuron 90 with a negative threshold bias produces an output in the absence of input from the other neurons. This feature is often observed in biological neurons and is also important for learning by backpropogation.
In preferred embodiments, each neuron 90 has an adjustable minimum output at threshold, Ex, that can be set to any value between 0 and Emax by application of a current to Ex via a transistor shown generally at 235. In the limit, the neuron 90 functions either as a Boolean switch when Ex =Emax, or as a summing amplifier when Ex is set to 0. Intermediate settings permit combined logic and arithmetic operations by the same unit. Similarly, this feature is also found in biological neurons which in many cases begin firing at a relatively high rate when the sum of inputs reaches the threshold.
In yet further preferred embodiments of neurons 90 provided in accordance with the present invention, the input-output transfer function as shown in FIG. 2A is linear between Ex and Emax. This conforms roughly to the relation between the average membrane depolarization and firing rate of a typical biological neuron tested in isolation. Generally, the linearity of the input-output function is not critical, but linearity contributes to ease of programming and stable operations especially in the time domain.
While sigmoidal transfer functions may provide better results for simulating learning algorithms, a linear transfer function where Ex 0 or Ex >0, will provide acceptable results provided that the derivative of the function was assumed to be that of a sigmoid. Sigmoidal transfer functions are also useful for, gradient descent learning since they enable the neurons 90 to perform multiplication and division of different inputs by biasing the operating region into the exponential or logarithmic portions of the sigmoid. As known by those with skill in the art, the sigmoidal transfer function can be obtained by adding one or more non-linear devices, for example, transistors, in parallel with the feedback resistor of a summing operational amplifier such as resistor 200 in FIG. 4.
The neurons 90 shown in FIG. 4 generally do not generate action potentials, but transmit their voltages as continuous variables. However, nerve fibers in the human body have extremely high impedances and reliable transmission is achieved by a pulse frequency modulation code wherein the output of a neuron 90 is transformed into an impulse frequency that is integrated by the synapse. There are, however, many examples such as in the retina, where outputs from short axon neurons are continuous potential changes. Except in cases where very precise temporal relations must be preserved, as for example in the computation of acoustic delays, an individual impulse has little significance, and thus the circuit of FIG. 4 provides adequate modelling of the action potential to achieve adequate pattern recognition.
When Ex is set high, the neurons 90 described herein respond with phase-locked pulses to sinusoidal inputs and therefore may also be used for acoustical delay computations. Thus, the neurons illustrated in FIG. 4 and provided in accordance with the present invention provide accurate and repeatable pattern recognition for a large variety of patterns which will be input to the system.
Synapse chip 40 is illustrated in FIG. 5. The synaptic weight of each synapse may be set by a serial input from the host computer 20 and stored in the synapse in a bit local memory 240. In preferred embodiments, the bit local memory 240 is six bits in length and the dynamic range of the synapse gains extends from 0 to 10 with 5-bit resolution, wherein the sixth bit determines the sign of the gain. The gains are implemented by current mirrors that scale the neuron output after it has been converted from a voltage to a current.
Modifiable synapse designs are known in the art. See, for example, Raffel J. I., Mann, J. R. Berger, R., Soares, A. M., Gilbert, S. A., "A Generic Architecture for Wafer-Scale Neuromorphic Systems," IEEE First International Conference on Neural Networks, III-501, San Diego, Calif. (1987). Modifiable synapse designs generally use either analog or digital signals to set the gains. In preferred embodiments, digital signals to set the gains are implemented with neural networks provided in accordance with the present invention because of greater reproduceability and because direct analog setting of the gains from the neuron outputs require an a priori knowledge of a commitment to a particular learning algorithm.
Each of the synapse gains is set by a 5-bit words stored in the local memories 240. Memories 240 are implemented as quasi-dynamic shift registers that read the data from the digital host computer 20 during the programming phase in order to set the gains of the synapses. Voltage to current converters 250 transform neuron outputs, shown generally at 260, into currents. Current mirrors 270 scale the currents with a 5-bit resolution. Weighted currents are summed on common lines SO1 shown generally at 280, to the neuron inputs.
In further preferred embodiments, each synapse chip 40 comprises 32�16 synapses with corresponding arrays of 6-bit memory elements, which are mapped onto the synapse matrices shown at 290. Thus, the chip 40 has 32 input lines NIj that come from neuron outputs routed over the switch modules. The inputs, which preferably vary between 0 and 4 volts, are transformed into currents as stated above. Only one voltage to current converter and current divider is needed per column, and associated with the converter is a current divider which generates required voltages to drive the synapses. Sixteen additional input lines may be provided in order to increase the fan-in for each neuron from 32 to 64 and up by placing one or more synaptic chips 40 adjacent to each other and connecting the outputs of one chip to the extended inputs of the other.
Voltage to current converters 250 take the neuron output voltages and generate currents proportional to those voltages. The circuit of FIG. 5 was derived from the design found in Bult, K. and Walinga, H., "A Class of Analog CMOS Circuits Based on the Square Law Characteristics of an MOS Transistor in Saturation," IEEE J. Solid-State Circuits, SC-22:3657 (1987).
The circuits of FIG. 5 having current mirrors 270 which generate currents that preferably decrease in a logarithmic fashion allow the selection of synaptic gains (weights) over a range of 0 to 10 with a 5-bit resolution. Synapses 290 comprise a series of current switches in series with a current source which comprises a steered current circuit using preferably PMOS transistors. A current switch steers the current to the neuron input line or to ground as controlled by synapse 290.
Current mirrors 270 invert the currents to implement excitatory or inhibitory connections to the neurons. In further preferred embodiments, the current sources in synapses 290 are realized by transistors whose gate and source terminals are connected to a current divider circuit in a current mirror configuration. By separating the current divider circuits from the synapse, sharing of divider circuits among all the synapses on the same column is accomplished. A current converter controlled by a sign bit allows implementation of excitatory and inhibitory connections without doubling the number of inputs. The switches that select the current levels and determine the synaptic weights are driven by the outputs of memory elements 240.
In further preferred embodiments, memory elements 240 may consist of cross-coupled inverters which are connected in series to form one large shift register. This allows the use of the same inverters to read the data serially in all memory elements by using a two-phase clocking scheme. Data for the two-phase clocking scheme may be provided by the digital host computer 20 over one line labelled "data" shown generally at 300.
FIG. 6A illustrates a graph of synaptic transfer functions. The linear nature of the synaptic transfer function occurs with synaptic weightings from 1/32 to 10. Furthermore, the synaptic transfer function is linear from 0 to 4 volts.
FIG. 6B illustrates transfer characteristics for synaptic modules modeled in accordance with the present invention and show that the transfer characteristics remain linear. The use of current mirrors permits arbitrary scaling of the synaptic gains (weights) with trade-off between range and resolution limited to five bits in preferred embodiments. In still further preferred embodiments, a minimum gain of 1/64 and a maximum of 10 is provided. The lower end of the dynamic range is determined by the number of possible inputs per neuron which when active should not drive the neuron output to its limit, whereas the high gain values are needed in situations where a single or only a few synapses must be effective such as in a copying action from one neuron to another.
FIG. 7 illustrates an approximation of a logarithmic scale using a digital code. The triangular graphs show that the total gain is the sum of five individual gains, each controlled by one bit. This leads inevitably to jumps in the gain curve. In the second case, shown by the square curve, a linear 3-bit gain is multiplied by four different constants controlled by the fourth and fifth bit. This "floating point" scheme provides better approximation to a logarithmic scale.
Although the resolution of an individual synapse is limited to five bits in preferred embodiments, several synapses driven by one neuron can be combined through switching, permitting greater resolution and dynamic range. Furthermore, mismatching of synaptic currents due to transistor differences can be compensated by this method.
In preferred embodiments, synaptic modules 40 are fabricated on CMOS or bi-CMOS integrated circuits and perform current scaling. The weight control is preferably digital having a 6-bit resolution with a dynamic range of weights or gains between 0 and 10. An output current range through the synaptic modules is preferably between 0 to 400 μA, with transfer characteristics being linear from 0 to 4 volts. Furthermore, the input impedance of the chips is greater than 1012 Ohms.
The switch modules 50 provided in accordance with the present invention serve to route signals between neuron modules 30 and synapse modules 40, thereby changing the connection architecture. Similar routing schemes have been employed for programmable interconnections in subcircuits between VLSI chips. See, for example, Sivilotti, M., "A Dynamically Configurable Architecture for Prototyping Analog Circuits," Advanced Research in VLSI, Proc. of the Fifth MIT Conference, Allen and Leighton eds., MIT Press, Cambridge, Mass. (1988).
FIG. 8 illustrates a block diagram of a switching module 50 which in preferred embodiments contains a 33 �33 crosspoint array of analog switches shown generally at 310. The 33�33 crosspoint array of analog switches are set by a serial digital input. The switching module 50 further comprises a number of serial-in, parallel-out shift registers (SIPO) 320, SIPO control logic 330, run control logic 340, a write strobe 350, and a gated two-phase clock generator 360.
Data is downloaded serially from the host computer 20 to SIPO 320 and SIPO control 330. The SIPO blocks 320 and 330 parallelize the data and transfer it to the switch array 310 under control of the write strobe generator 350. The switching fabric of switch array 310 preferably comprise 1-bit switch control memories and analog switches coupled together. As known by those with skill in the art, control data can connect an arbitrary horizontal line to a vertical line by writing a "1" to the appropriate memory cell on the switch fabric. Switches in the switch fabric are generally placed in series with horizontal signals which allow the host processor to input a horizontal or vertical trace in the switch chip 310. Thus, interconnection busses may be partitioned into several segments which increase the maximum number of obtainable connections.
In preferred embodiments each switching cell in the switching fabric 310 is implemented as a CMOS transmission gate connected to one bit of memory. A control logic subsystem enables chip load circuits where the input is active, disables the chip load circuits when the loading is done, and propagates signals to the next switch chip. The signals U00 . . . U31 pass vertically through the chip to D00 . . . D31. Similarly, the signals L00 . . . L31 pass horizontally through the chip to R00 . . . R31.
FIG. 11A illustrates a block diagram of switching fabric 310 in finer detail. Circuits 520 represent in preferred embodiments the aforementioned 1-bit switch control and analog switch. Control data connects an arbitrary horizontal line to a vertical line by writing a "one" into the appropriate memory cell. The circles 530 are also switches and memory cells. Switches in series with the horizontal or vertical signals allow the digital serial computer 20 to cut a horizontal or vertical trace in the switch chip. This allows interconnection busses to be partitioned to several segments which increases the maximum number of allowed connections. Additionally, switching fabric 310 contains circuits 540 which control the time constants, τ, of the synapse transfer function.
For the analysis or generation of temporal patterns as they occur in motion or speech, for example, adjustable time constants of the synaptic transfer function must be provided to the general purpose analog computer of the invention. In preferred embodiments, circuits 540 provide low pass filtering of the input signal to the synapse with a 4-bit control of a time constant over a specified time range. In further preferred embodiments, this time ranges from 50 microseconds to 500 milliseconds or about 4 orders of magnitude. There are several ways to implement large and adjustable time constants to provide synaptic transfer function adjustability. One way is to charge or discharge a capacitor to a transconductance amplifier connected as a unity gain buffer. In this fashion a very low gain bandwidth (GBW) and slew rate low pass filter can be obtained. With this type of circuit, an input step may be applied to the amplifier so that the amplifier will first slew and then evolve exponentially towards its final value with a time constant proportional to the inverse of the GBW. By adjusting the bias currents of the amplifier one can, in effect, change the time constant of the circuit.
Another way to obtain low pass filtering adjustable synaptic transfer functions is based on translinear circuits. By biasing MOS transistors into weak inversion, the voltage current characteristics are exponentially similar to a bipolar transistor. This allows the use of flexible bipolar transistors to implement different functions.
By combining a low pass input with a direct input of opposite sign, both originating from the same neuron, typical "on" and "off" responses which serve as measures of time after the beginning and end of events and which are common in biological neurons can be obtained. Low pass circuits having this configuration are shown in FIG. 11B. In FIG. 11B, a block diagram of a circuit comprising neurons, synapses, and a low pass synaptic transfer functions to obtain on and off responses is shown. A transfer function is shown generally at 555 denoted by "X-1" for general shifting of data according to the desired application. The neurons are represented as input buffers A at 550 and output buffers B at 560.
The variable synaptic gains are implemented in preferred embodiments by a variable resistor 570 coupled to a variable capacitor 580 in a low pass filter configuration. The resistor capacitor and low pass filter combinations provide variable synaptic gains or "weights" for the circuit and may be programmably adjusted by the digital serial computer to effect the proper synaptic weights for the desired application. As an example of the input-output relationship, a squarewave input 575 is input to buffers 550 and the resulting exponentially decaying outputs 585 through buffers 560 is obtained. The shift in the exponentially decaying output from the lower buffer 560 as compared to the higher buffer 560 shows that the transfer function of the synapse 550 is on different legs of the circuit.
FIG. 8 illustrates SIPO, 320 which parallelizes serial data received from the host computer 20 to 33-bit words. Each SIPO bit drives one row of switch memories. Additionally, several SIPO taps may be used to generate the control signals. These control signals may then be used to detect when the first 33 bits of a cycle have been received from the host computer 20 to count the 36 clocks that comprise a cycle.
The write strobe generator circuit 350 maintains the address of the next column to receive SIPO data. After a 33-bit word has been assembled by the SIPO 320, the write strobe circuit 350 writes it to the proper column of switch memory 310 by asserting a control signal. In preferred embodiments, this function may be implemented by shifting a "1" into a 33-bit chip register. The output of the write strobe generator shown generally 370, may be generated after all 33 columns have been loaded.
Two-phase clock generator 360 produces a non-overlapping, two-phase clock. Furthermore, two-phase clock generator 360 includes logic which enables the clock only on the microprocessor's loading of the switch memory. This reduces the chip's power consumption. In preferred embodiments the clock signal 380 is a systemwide, 2 MHz, 50% duty cycle clock. During each 36 CLK cycles, 33 bits of switch control memory are loaded. In preferred embodiments the data provided by the host computer 20 during the last 3 CLKs of a cycle are not used. This allows the CPU to nibble-align the switch data in its local memory. The amount of memory used by the host computer 20 to maintain the image of the switch memory is 33�36=1188 bits. Thus, approximately 35 KBytes are necessary in a system consisting of 12 switch chips/row�20 rows/card=240 switch chips.
FIG. 9A illustrates a schematic of the interconnections between the neuron modules 30, synapse modules 40 and the switch modules 50. Input signals 390 are input to the switch modules 50. Outputs can be monitored directly from the switches at 400, or from the neuron modules 30 at 410. Switch 50 and synapse connections 40 may be controlled from the, host computer 20.
FIG. 9B illustrates neuron output control through the adjustment of the synaptic gain. The synaptic gain was first set at 1/32 at 420. At arrow 430 the gain was switched to 1/8 while at arrow 440 the gain was switched to 1/2, and at arrow 450 the gain was switched to 1.8. The input was a triangle wave 460 and the output of the neuron between 0 and 4 volts varied according to the synaptic gains which were switched. Thus, the neural networks of FIG. 9A and FIG. 1 behave like a biological neural network given a triangle wave input.
The connections, synaptic gains, neuron parameters and time constants may be set from the host computer 20 either manually, or through implementation of learning algorithms that drive these parameters on the basis of neuron outputs. The connections are routed by graphic control routing routines as commonly used in circuit board design.
Neural networks provided in accordance with the present invention are particularly useful for feature-specific receptor fields, temporal pattern analysis, or circuits for motion control as in robotics. Input to a neural network provided in accordance with this invention can come from sensory transducer arrays such as an electronic retina, cochlea, or tactile sensors.
To determine transfer functions as a function of voltage, consider an N neuron system wherein each neuron receives M inputs. Each input may have an RC stage generating time constants arranged at 1 millisecond to 1 second in preferred embodiments, and a gain stage (Gij), which establishes the input's weight. The weighted sum of neuron inputs is fed into an amplifier which may have a linear or sigmoidal transfer function. The network is then described with N x M differential equations which yield the voltages on the capacitors as a function of time and the neuron outputs.
FIG. 10 illustrates an electrical model of a simulated neural network 470. Low pass filters, are comprised of capacitors 480 and resistors 490, while the synaptic gains are shown generally at 500. Summing amplifiers 510 sum the outputs from the low pass filters.
The voltage on the jth capacitor of the ith neuron, Vij, is given by:
dVij /dt=-Vij /Cij �(1/Rij +1/R'ij)+Nx /Cij �Rij
where Nx is the voltage from the neuron driving the input. The output of the jth neuron is thus given by: ##EQU1## where S(x)=1/(1+exp(-x).
Utilizing the above voltage models for the simulated neural network at FIG. 10 wherein the gains are uniformly distributed while the interconnections are randomly selected, the host processor 20 is able to rapidly and efficiently solve variously sized networks with randomly selected time constants. This result has not heretofore been achieved in the art, and thus methods and apparatus provided in accordance with the present invention solve a long-felt need in the art for general purpose analog neural computers.
There have thus been described certain preferred embodiments of general purpose analog computers provided in accordance with the, present invention. While preferred embodiments have been described herein, it will be recognized by those with skill in the art that modifications are within the true spirit and scope of the invention. The appended claims are intended to cover all such modifications.
Non-Patent Citations
Referenced by
Legal Events
Original Image


text:
A preserving solution comprising a microbicidally or fungicidally effective amount of a biguanide or water-soluble salt thereof, in combination with a buffer system, said biguanide having the formula: ##STR1## wherein n is from 1 to 500, said biguanide being present in an amount from 0.000001 to 0.0003 weight percent, useful for preserving, for example, a cosmetic formulation.
1. A solution comprising a microbicidally or fungicidally effective amount of a biguanide or water-soluble salt thereof, in combination with a borate buffer system, said biguanide having the formula: ##STR10## wherein n is from 1 to 500, said biguanide being present in an amount from 0.000001 to 0.0003 weight percent.
2. The solution of claim 1 wherein the biguanide is a polymeric water-soluble salt.
3. The solution of claim 2 wherein the biguanide is a water-soluble salt of polyhexamethylene biguanide.
4. The solution of claim 1 wherein the biguanide is a water-soluble monomer.
5. The solution of claim 2 wherein the biguanide is a polymer having molecular weights under 100,000.
6. The solution of claim 5 wherein the biguanide is a polymer having molecular weights in the range from 1,000 to 50,000.
7. The solution of claim 5 wherein n of the biguanide polymer averages between 2 and 12.
8. The solution of claim 3 wherein n averages from 4 to 7.
9. The solution of claim 3 containing at least 0.00001 weight percent of the biguanide polymer.
10. The solution of claim 9 wherein the biguanide polymer is present in an amount from about 0.0001 to about 0.0003 weight percent.
11. The solution of claim 1 containing microbicidally effective mixtures of a biguanide or water-soluble salt thereof and at least one other germicidal agent.
12. The solution of claim 2 wherein the biguanide is a water-soluble salt of polyhexamethylene biguanide wherein n averages between 2 and 12.
13. A solution according to claim 3 wherein the biguanide is effective to preserve the solution against S. aureus, P. aeruginosa and E. coli organisms.
14. A solution according to claim 3 which is effective as a disinfecting solution against S. epidermis and C. albicans organisms.
15. A solution according to claim 1 in which the biguanide is a preservative for the solution.
16. An aqueous solution according to claim 15.
17. A solution according to claim 15 in which the solution is an aqueous solution for contact lens care and contains additionally at least one component from the group consisting of amphoteric, nonionic and cationic surfactants, tonicity agents, sequestering agents and viscosity builders.
18. A solution according to claim 1 in which the solution is an aqueous solution for disinfecting contact lenses and contains additionally at least one component from the group consisting of amphoteric, nonionic and cationic surfactants, tonicity agents, sequestering agents and viscosity builders.
This is a continuation of co-pending application Ser. No. 680,450 filed Dec. 11, 1984 now abandoned, which is a continuation-in-part of our copending application, Ser. No. 655,965, filed Sept. 28, 1984 now abandoned.
1. Field of the Invention
This invention relates generally to improved disinfecting and/or preserving systems. More specifically, the invention pertains to the use of such systems in solutions for contact lenses and contact lens care.
2. Description of Related Art
Generally, contact lenses in wide use fall into two categories: the hard or rigid corneal type lenses formed from materials prepared by polymerization of acrylic esters, such as polymethyl methacrylate (PMMA), and gel, hydrogel or soft type lenses made of polymerized hydrophilic or hydrophobic monomers, such as 2-hydroxyethyl methacrylate (HEMA). The hard acrylic type contact lenses are characterized by low water vapor diffusion constants, resistance to the effects of light, oxygen and hydrolysis and absorb only minor amounts of aqueous fluids. Because of the durability of hard contact lenses, coupled with their tendency not to absorb appreciable amounts of water, the selection of suitable disinfecting agents, cleaning agents or other lens care compounds is relatively non-critical.
However, unlike hard lenses, soft type contact lenses and certain of the newer gas permeable hard contact lenses have a tendency to bind and concentrate significantly more fluids, environmental pollutants, water impurities as well as antimicrobial agents and other active ingredients commonly found in lens care solutions. In most instances, the low levels of the ingredients in lens care solutions do not lead to eye tissue irritation when used properly. Nevertheless, because of the inherent binding action of protein deposits and soft lens materials disinfecting agents and preservatives tend to build up on lens surfaces and become concentrated to potentially hazardous levels, such that when released can cause corneal inflammation and other eye tissue irritation.
Previous efforts to alleviate the problem of binding and concentrating disinfectants and preservatives onto contact lens surfaces, and reducing the potential for eye tissue irritation have not been totally satisfactory. For example, in spite of low toxicity levels not all disinfectants are compatible for use with all types of contact lenses. Many hard lens disinfecting and preservative solutions contain benzalkonium chloride or chlorobutanol. Although they are effective antibacterial agents, their use can result in a loss of lens hydrophilic properties, cause solution instability or may even lack compatibility with certain types of hard lenses, e.g., high silicon content.
Other antibacterial agents were found to be more compatible with contact lenses and exhibit less binding on lens surfaces. In one case, it was found that chlorhexidine, a biguanide, binds to soft lens material seven times less than benzalkonium chloride, but the presence of proteinaceous oily tear-film deposits can double the amount of chlorhexidine absorbed over that of clean lenses. U.S. Pat. No. 4,354,952 discloses very dilute disinfecting and cleaning solutions containing chlorhexidine or its salts in combination with certain amphoteric and non-ionic surfactants. These solutions were found to reduce the amount of binding of chlorhexidine on hydrophilic soft contact lenses. Notwithstanding the reduction in binding achieved by this invention, the use of chlorhexidine did result in certain tradeoffs. That is, the antimicrobial activity of the chlorhexidine may be diminished when used with certain amphoteric surfactants. Furthermore, if not used inproper ratio, the surfactant and disinfectant will precipitate unless a non-ionic type surfactant is also employed.
U.S. Pat. No. 4,361,548 discloses a contact lens disinfectant and preservative containing dilute aqueous solutions of a polymer; namely, dimethyldiallylammonium chloride (DMDAAC) having molecular weights ranging from about 10,000 to 1,000,000. Amounts of DMDAAC homopolymer as low as 0.00001 percent by weight may be employed when an enhancer, such as thimerosal, sorbic acid or phenylmercuric salt is used therewith. Although lens binding and concomitant eye tissue irritation with DMDAAC were reduced, it was found in some users to be above desirable clinical levels.
British Pat. No. 1,432,345 discloses contact lens disinfecting compositions containing a polymeric biguanide (of the type contemplated by applicants) and a phosphate buffer. The concentration of the disinfecting polymer disclosed by this patent is substantially higher than that of the present invention. The products embraced by this patent have not found acceptance by the consumer. Corneal staining is an indication of patient acceptability and compositions as disclosed by this patent have staining value of 17% or more present, far above that which is desirable for patient acceptability, see Table V in the Examples of this application.
Other efforts to reduce or eliminate soft lens binding have led to the use of anti-binding or detoxifying agents, like polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA). However, these polymers alone were found to be ineffective for the most part, in reducing lens binding and eye tissue irritation.
Accordingly, there is a need for improved disinfecting and preservative solutions which are compatible for use with most types of contact lenses while maintaining both a high level of antibacterial activity and low order of toxicity to eye tissue with little or no binding or concentrating of the disinfecting agent onto lens surfaces.
Accordingly, there is a need for improved preservative systems that maintain a low order of toxicity and irritation to tissue in and surrounding the eye, i.e., the eye itself, the upper eyelid, the lower eyelid, etc.
The present invention provides for improved solutions for disinfecting and/or preserving contact lenses. The solutions are compatible with both hard and soft type lenses, and are adaptable for use with virtually any of the commonly known disinfecting techniques, including "cold" soaking under ambient temperature conditions, as well as with high temperature disinfecting methods. The disinfecting and preservative solutions of the present invention are especially noteworthy for their wide spectrum of bactericidal and fungicidal activity at low concentrations coupled with very low toxicity and reduced affinity for binding and concentrating when used with soft type contact lenses. Our co-pending application, Ser. No. 655,965, filed Sept. 28, 1984, deals more specifically with improved disinfecting and/or preserving solutions for contact lenses and contact lens care.
In addition to solutions for contact lenses, the instant invention provides for improved preservative systems for cosmetic products, specifically intended for those products used near the eyes. The advantage to this preservative system is its wide spectrum of bactericidal and fungicidal activity at low concentrations coupled with very low toxicity and irritation.
In accordance with this invention, there is provided an aqueous solution for disinfecting and/or preserving items such as contact lenses and cosmetic products comprising microbicidally effective amounts of a biguanide or water-soluble salts thereof having the following general formula: ##STR2## wherein n is from 1 to 500 in combination with a buffer.
The biguanides for use in the present invention include hexamethylene biguanides, their polymers and water-soluble salts of such base compounds and polymers. Generally, the polymers have molecular weights of up to about 100,000 and are present in amounts from almost 0.000001 to about 0.0003 weight percent. Typically, the solutions will be made isotonic with lacrimal fluids. The antibacterial action of the biguanide-containing solutions described herein may also be supplemented by the addition of other germicidal agents. Because the overall germicidal activity of such combinations will in some instances be greater than when each is used separately, the concentration of total disinfectant in solution can be lowered further reducing the potential for binding, concentrating and adverse toxic reactions.
The disinfecting solutions of the present invention are effective at low concentrations against a wide spectrum of microorganisms, including but not limited to S. epidermidis, C. Albicans, A. fumigatus, etc. The solutions contain as their principal microbicide a biguanide of formula I.
That is to say, the present invention contemplates low molecular weight oligomers where n averages from 4 to 7, high molecular weight long chain polymers up to approximately 100,000 M.W., as well as individual monomers of such polymers where n is 1. In addition to the above, the present invention also includes water-soluble salts of the free bases, such as hydrochloride and borate salts, acetate, gluconate, sulfonate, tartrate and citrate salts. Most conveniently, however, the water-soluble salts, e.g., hydrochloride, of the foregoing biguanides are used in the disinfecting/preservative solutions wherein the value for n generally averages between 2 and 12, and more specifically from 3 to 8. Thus, one preferred group of water-soluble biguanides described herein will have average molecular weights of at least 1,000 and more particularly from 1,000 to 50,000 M.W.
The range of polymeric and monomeric biguanides within the foregoing broad definition for use in the solutions of the present invention is rather surprising and unexpected, since polymers in the higher molecular weight ranges usually demonstrate less binding and lower toxicity levels than corresponding lower molecular weight materials. However, the monomer, e.g., hexamethylene biguanide hydrochloride, provides good bactericidal activity at low concentrations and with little binding effect, as does polyhexamethylene biguanide hydrochloride wherein n averages 4 to 7.
The above-described biguanides and methods of preparation are described in the literature. For example, U.S. Pat. No. 3,428,576 describes the preparation of such biguanides from a diamine and salts thereof and a diamine salt of dicyanimide. This patent expressly teaches methods for making, e.g., the hydrochloride salt of polyhexamethylene biguanide which is also commercially available from ICI Americas, Inc., Wilmington, DE 19897, under the trademark Cosmocil CQ. For convenience purposes only, the biguanides described hereinafter for disinfecting and/or preserving contact lenses shall be referred to as "PHMB."
The preserving solutions of the instant invention are effective in concentrations as low as 0.000001 weight percent PHMB. Generally, the disinfectant and preservative solutions will contain from about 0.00001 to about 0.0003 weight percent (i.e., three parts per million -ppm) PHMB. It has also been found that the bactericidal activity of the solutions may be enhanced or spectrum of activity broadened through the use of a potentiating amount of a second disinfectant or germicidal agent. As a result, the total concentration of disinfectant required when PHMB is used in combination with other germicidal agents may be lowered further due to complementary bactericidal activity, which is most desirable in achieving the lowest possible potential for lens binding, concentrating and particularly skin, eye or eyelid tissue inflammation. Thus, the effective concentration of PHMB may be lowered to about 0.000001 weight percent and up to about 0.0003 weight percent.
The disinfecting/preserving solutions of this invention contain a buffer, preferably a borate buffer, e.g., boric acid, sodium borate, potassium tetraborate, potassium metaborate or mixtures of the same. Applicants were surprised to find that, at the amounts of PHMB present in the solutions of this invention, a borate buffer system was exceptionally effective. This is particularly surprising in view of British Pat. No. 1,432,345 disclosing phosphate buffers for solutions containing higher amounts of PHMB. Whatever the reasons, PHMB solutions buffered only with phosphate are ineffective under the conditions of this invention, see Table I of the examples below.
Applicants have additionally found to their surprise that conventional buffers can be useful in this invention when those buffers are only used in conjunction with increased, but within concentrations of this invention, amounts of PHMB, an increased amount of sequestering agent, an amphoteric surfactant, a non-ionic surfactant or a cationic surfactant. The buffers in this category are sodium or potassium citrate, citric acid, sodium bicarbonate and various mixed phosphate buffers, including combinations of Na2 HPO4, NaH2 PO4 and KH2 PO4. Generally, buffers may be used in amounts ranging from about 0.05 to about 2.5 percent, and more preferably, from about 0.1 to about 1.5 percent (w/w). Suitable sequestering agents include ethylene diaminetetraacetic acid (EDTA), gluconic acid, citric acid, tartaric acid and their salts; e.g., sodium. The foregoing surfactants, when employed as a buffer enhancer will be present in an amount from 0.0001 percent to 5.0 percent (w/w). Additionally, the nonionic surfactant can be employed both as a buffer enhancer and as a cleaning agent or a combined cleaner and disinfecting/preserving solution.
The amphoteric charged surfactant molecule consists of a relatively complex organic portion with a net positive or negative charge. The latter charge is balanced by a positive or negative counterion; (e.g., Na+, Cl-) which is not connected to the molecule by a covalent bond but is held in its environment by the attraction between the oppositely charged moieties. In the amphoteric molecule, the complex organic portion referred to above contains both positive and negative charges (at least one of each). As with the singly-charged molecule, electrical neutrality is provided by counterions, both negative and positive counterions being required for the same molecule. The uncharged portion of the amphoteric molecule contains hydrophobic groups (the charged portions usually function as a part of the hydrophilic groups) and may contain non-charged (i.e. non-ionic) hydrophilic groups.
A preferred amphoteric surfactant molecule of this invention is illustrated by the following chemical structures: ##STR3## The structure is illustrated in the ionized form as it exists in aqueous media. In this structure, R represents a fatty acid radical of C6 -C18, e.g., coconut oil which is a mixture of lauric, myristic, oleic, stearic, palmitic and other similar acids; lauric acid; capric acid; caprylic and ethylhexoic acid; oleic acid; linoleic acid and stearic acid; R2 is ##STR4## M and M1 are cation salt forming groups, such as hydrogen or alkali metals, X is OH, or the acid group of an anionic surface active agent, e.g., sodium lauryl sulfate or sodium lauryl sulfonate, R1 is H or ##STR5## provided, however, when R1 is hydrogen, M1 is absent and n is an integer from 1 to 40. Materials of this type are offered commercially from the Miranol Chemical Co., Doyton, NJ 08810 under the trade name "Miranol." Typical examples of ionized amphoteric salts (commercial trade names Miranol 2MCA and C2M respectively) are shown below: ##STR6## Broadly, these compounds can be monocarboxylate, dicarboxylates or sulfonates. The counterions in the first example are Na+ and CH12 H25 OSO3 - and in the second example Na+ and OH-.
Another class of amphoteric surfactants is given by the following chemical structure in the ionized form: ##STR7## where R is a hydrophobe radical such as methyl octadecyl, methyldodecyl, methyloctadecenyl, etc.; M is an alkali metal, such as Na, K, etc.; X is the negative part of an agent, such as CH3 OSO3, C2 H5 OSO3, Cl, Br, etc.; n is an integer from 1 to 40. Materials of this type are available commercially from Armstrong Chemical Co., Inc., Janesville, WI 53545 under the trade name Sanac. This molecule has a nonionic functionality, (C2 H4 O)n H. Specific examples are [2-(2-carboxyethyl) ethyl] [2-(2-hydroxyethyl)ethyl]methyloctadecylammonium methyl sulfate, potassium salt; [2-(2- carboxyethyoxy) ethyl] [2-(2-hydroxyethoxy) ethyl] methyloctadecenylammonium methyl sulfate, potassium salt; and [2-(2- carboxyethyoxy) ethyl] [2-(-hydroxyethoxy) ethyl] methylododecylammonium methyl sulfate, potassium salt.
Another class of amphoteric surfactants may be exemplified by the following chemical structure, in the ionized form: ##STR8## where R1 is a fatty acid radical or other hydrophobe radical, R2 is an alkyl or substituted alkyl radical, Z is a sulfate or sulfonic group, e.g., --SO4, --CH2 CH2 SO3 ; M is an alkali metal such as Na or K, X is the negative radical from a quaternizing reagent such as CH3 OSO3, C2 H5 OSO3, Cl, Br, etc.
Yet another class of amphoteric surfactants may be exemplified by the following chemical structure in the ionized form: ##STR9## where R is alkylene having 12 to 13 atoms and R--CO-- taken together as the acid radical such as coconut acid. Materials of this type are exemplified by cocoamidopropyl betaine commercially available from Stephen Chemical Co., Northfield, IL 60093 under the trade name Amphosol CA.
As suitable cationic surfactants, dual quaternary ammonium compositions are described in U.S. Pat. Nos. 3,525,793 and 3,472,939 and are commercially available from Onyx Chemical Company, Jersey City, N.J. under the trademark BTC 2125M.
The second disinfectant/germicide can be employed as a solution preservative, but it may also function to potentiate, complement or broaden the spectrum of microbicidal activity of PHMB. This includes microbicidally effective amounts of germicides which are compatible with and do not precipitate in the presence of PHMB, and comprises concentrations ranging from about 0.00001 to about 0.5 weight percent, and more preferably, from about 0.0001 to about 0.1 weight percent. Suitable complementary germicidal agents include, but are not limited to thimerosal, sorbic acid, 1,5-pentanediol, alkyl triethanolamines, phenylmercuric salts, e.g., nitrate, borate, acetate, chloride and mixtures thereof. Other germicidal compounds and salts may be used. Suitable salts are soluble in water at ambient temperature to the extent of at least 0.5 weight percent. These salts include the gluconate, isothionate (2-hydroxyethanesulfonate), formate, acetate, glutamate, succinanate, monodiglycollate, dimethanesulfonate, lactate, diisobutyrate and glucoheptonate.
Further embodiments of potentiating or complementary disinfecting agents for use with PHMB also include certain quaternary ammonium compounds which possess a generally wide spectrum of bactericidal activity and wetting properties. Representative examples of the quaternary ammonium compounds are compositions comprised of balanced mixtures of n-alkyl dimethyl benzyl ammonium chlorides.
The aqueous solutions of the present invention when used for treating contact lenses are also adjusted with tonicity agents to approximate the osmotic pressure of normal lacrimal fluids which is equivalent to a 0.9 percent solution of sodium chloride or 2.5 percent of glycerol solution. The solutions are made substantially isotonic with physiological saline used alone or in combination, otherwise if simply blended with sterile water and made hypotonic or made hypertonic the lenses will lose their desirable optical parameters. Correspondingly, excess saline may result in the formation of a hypertonic solution which will cause stinging and eye irritation.
The aqueous isotonic solutions of PHMB with optional germicidal agents are useful disinfectants for both hard and soft contact lenses without any further additives. Nevertheless, the solutions of the present invention may be formulated into specific contact lens care products, such as wetting solutions, soaking solutions, cleaning and conditioning solutions, as well as all purpose type lens care solutions, etc. and mixtures thereof. Such additives make the solutions more acceptable to the user in terms of greater comfort. However, the additives must be non-toxic and compatible with contact lenses.
When used, neutral or non-ionic surfactants impart cleaning and conditioning properties and are usually present in amounts up to 15 weight percent. The surfactant should be soluble in the lens care solution, non-irritating to eye tissues and still usually have a hydrophilic-lipophile balance (HLB) of 12.4 to 18.8. Satisfactory non-ionic surfactants include polyethylene glycol esters of fatty acids, e.g. coconut, polysorbate, polyoxyethylene or polyoxypropylene ethers of higher alkanes (c12 -C18). Examples of the preferred class include polysorbate 20 (available from ICI Americas Inc., Wilmington, DE 19897 under the trademark Tween 20), polyoxyethylene (23) lauryl ether (Brij� 35), polyoxyethylene (40) stearate (Myrj� 52), polyoxyethylene (25) propylene glycol stearate (Atlas� G 2612). Brij� 35, Myrj� 52 and Atlas� G 2612 are trademarks of, and are commercially available from, ICI Americas Inc., Wilmington, DE 19897.
One non-ionic surfactant in particular, consisting of a poly (oxypropylene) -poly (oxyethylene) adduct of ethylene diamine having a molecular weight from about 7,500 to about 27,000 wherein at least 40 weight percent of said adduct is poly (oxyethylene), has been found to be particularly advantageous for use in cleaning and conditioning both soft and hard contact lenses when used in amounts from about 0.01 to about 15 weight percent. The CTFA Cosmetic Ingredient Dictionary's adopted name for this group of surfactants is polyoxamine. Such surfactants are available from BASF Wyandotte Corp., Wyandotte, Mich., under the registered trademark "Tetronic." An analogous series of surfactants is the poloxamer series which is a polyoxyethylene, polyoxypropylene block polymers available from BASF Wyandotte Corp., Parsippany, NJ 07054 under the trademark "Pluronic."
Oher amphoteric, cationic and nonionic surfactants suitable for in the invention can be readily ascertained, in view of the foregoing description, from McCutcheon's Detergents and Emulsifiers, North American Edition, McCutcheon Division, MC Publishing Co., Glen Rock, NJ 07452.
It may also be desirable to include water-soluble viscosity builders in the PHMB-containing solutions of the present invention. Because of their demulcent effect, viscosity buildiers have a tendency to enhance the lens wearer's comfort by means of a film on the lens surface cushioning impact against the eye. Included among the water-soluble viscosity builders are the cellulose polymers like hydroxyethyl or hydroxypropyl cellulose, carboxymethyl cellulose and the like. Such viscosity builders may be employed in amounts ranging from about 0.01 to about 4.0 weight percent or less.
This invention relates to disinfecting and/or preserving solutions for use with most contact lenses, including hard and soft lenses, as well as the newer hard gas permeable type contact lenses, such as described in U.S. Pat. No. 4,327,203. The term "soft contact lens" as used herein generally refers to those contact lenses which readily flex under small amounts of force and return to their original shape when that force is released. Typically, soft contact lenses are formulated from poly (hydroxyethyl methacrylate) which has been, in the preferred formulations, crosslinked with ethylene glycol dimethacrylate. For convenience, this polymer is generally known as PHEMA. Soft contact lenses are also made from silicon polymers crosslinked, for example, with dimethyl polysiloxane. Convention "hard contact lenses," which cover only the cornea of the eye, usually consist of poly (methyl methacrylate) crosslinked with ethylene glycol dimethacrylate.
The aqueous PHMB-containing solutions can be effectively used in disinfecting contact lenses by any of the well recognized methods. For example, lenses may be treated by the "cold" soaking method at room temperature for a period ranging from 4 to 12 hours. The lenses are then removed from the solution, washed in preserved isotonic saline solution and then replaced on the eye.
In addition to the cold soaking method, the solutions disclosed herein are adaptable for use in other types of equipment, such as ultrasonic cleaners. Because the solutions are also stable when heated, they are adaptable for use with high temperature disinfecting methods. Typically, lenses are heated to 80� in a disinfecting unit containing the solution for a time period of at least ten minutes, removed and rinsed with isotonic saline.
In addition, the present invention contemplates the use of the PHMD buffer preservative system in ophthalmologic products and dermatologic formulations applied near the eye. Such use will, of course, depend upon the compatibility of the preservative system with the active ingredient(s) in the product.
The following examples demonstrate the compositions and methods of the instant invention. However, it is to be understood that these examples are for illustrative purposes only and do not purport to be wholly definitive as to conditions and scope of this invention.
An aqueous contact lens disinfectant solution is prepared having the following formulation:
______________________________________ Percent (w/v)______________________________________Polyhexamethylene Biguanide HCl* .0001Poloxamine 1107** .5Na2 EDTA .011Boric Acid 1.10Sodium Borate .40Sodium Chloride .30Distilled Water qs 100.0______________________________________ *n = 4.5 to 6.5 **Flake grade, molecular weight 14,500, 70% (wt.), Tetronic � 1107, a poly (oxypropylene) poly (oxyethylene) block copolymer adduct of ethylen diamine, a trademark of BASF Wyandotte Corp., Wyandotte, MI.
The solution is prepared by gradually heating 80 percent of the water to 80� C. while dissolving the disodium EDTA therein. The boric acid and sodium borate are added to the heated solution of disodium EDTA and dissolved. The sodium chloride is then added to the solution and dissolved, followed by the addition of surfactants. After the solution is cooled to room temperature, the polyhexamethylene biguanide is added, followed by the balance of distilled water. The solution is sterilized by forcing through an 0.22 micron cellulose acetate filter by means of a peristaltic pump and packaged in sterilized plastic containers.
The bactericidal activity of the above solution is tested by exposing S. epidermidis (1.6�106 microorganisms/ml) and C. albicans (1.1�106 microorganisms/ml) each to 20 ml of said solution at room temperature for 5 hours. Subsequently, an aliquot sample of each is placed on an agar plate and incubated for 48 hours at elevated temperatures. At the conclusion of the incubation period, the plates are examined for the development of colonies. The results showed 6 log reduction of S. epidermidis microorganisms and 1.3 log reduction of C. albicans microorganisms.
An aqueous contact lens disinfecting solution is prepared with the following formulation:
______________________________________ Percent (w/v)______________________________________Polyhexamethylene Biguanide HCl* .0001Na2 EDTA .11Boric Acid 1.1Sodium Borate .40Sodium Chloride .30Distilled Water qs 100.0______________________________________ *n = 4.5 to 5.6
The above formulation may be prepared by the method described in Example I.
An aqueous contact lens disinfecting solution is prepared with the following formulation:
______________________________________ Percent (w/v)______________________________________Polyhexamethylene Biguanide HCl* .00009Poloxamine 1107 .5Na2 EDTA .11Boric Acid .64Sodium Borate .16Sodium Chloride .49Distilled Water qs 100.0______________________________________ *n = 500
The above formulation may be prepared by the method described in Example I.
An aqueous contact lens disinfecting solution is prepared with the following formulation:
______________________________________ Percent (w/v)______________________________________Polyhexamethylene Biguanide HCl* .00009Na2 EDTA .11Boric Acid .64Sodium Borate .16Sodium Chloride .49Distilled Water qs 100.0______________________________________ *n = 50
The solution is prepared by dissolving the sodium borate in approximately 80 percent of the distilled water. The disodium EDTA is then added to the sodium borate solution, followed by dissolving the boric acid and sodium chloride therein. The polyhexamethylene biguanide is added, followed by the balance of distilled water. The solution may be sterilized according to the method described in Example I.
In this example, the effectiveness of polyhexamethylene biguanide hydrochloride (n=4.5 to 6.5) as a preserving agent is evaluated, using (1) a borate buffer system and (2) a phosphate buffer system. Each preserved solution is prepared by the method of Example I and each is adjusted so as to be isotonic. All ingredients are by weight percent unless otherwise noted. Following the microbial test methods of Example I, each solution is evaluated for preservative effectiveness against S. aureus, P. aeruginosa and E. coli organisms after 14 and after 28 days. To be considered effective in this test, there must be at least 3 log reduction in number of organisms for each type of organism at 14 days and at 28 days. The solutions and test results are tabulated in Table I (Solutions) and Table IA (Results) below.
TABLE I______________________________________PHMB PRESERVED SOLUTIONSFORMULATION.sup.(1) Mono- Sodium Dibasic basicSol. Boric Sodium Chlor- Na2 (PPM) Phos- Phos-# Acid Borate ide EDTA PHMB phate phate______________________________________ 1 1.1% 0.40% 0.30% 0.11% 0.99 -- -- 2 1.1% 0.40% 0.30% 0.11% 0.88 -- -- 3 1.1% 0.40% 0.30% 0.11% 0.77 -- -- 4 1.1% 0.40% 0.30% 0.11% 0.66 -- -- 5 1.1% 0.40% 0.30% 0.11% 0.55 -- -- 6 1.1% 0.40% 0.30% 0.11% 0.44 -- -- 7 1.1% 0.40% 0.30% 0.11% 0.33 -- -- 8 1.1% 0.40% 0.30% 0.11% 0.22 -- -- 9 1.1% 0.40% 0.30% 0.11% 0.11 -- --10 1.1% 0.40% 0.30% 0.11% 0.05 -- --11 -- -- 0.55% 0.11% 0.99 0.65% 0.1%12 -- -- 0.55% 0.11% 0.88 0.65% 0.1%13 -- -- 0.55% 0.11% 0.77 0.65% 0.1%14 -- -- 0.55% 0.11% 0.66 0.65% 0.1%15 -- -- 0.55% 0.11% 0.55 0.65% 0.1%16 -- -- 0.55% 0.11% 0.44 0.65% 0.1%17 -- -- 0.55% 0.11% 0.33 0.65% 0.1%18 -- -- 0.55% 0.11% 0.22 0.65% 0.1%19 -- -- 0.55% 0.11% 0.11 0.65% 0.1%20 -- -- 0.55% 0.11% 0.05 0.65% 0.1%______________________________________ Note: .sup.(1) Distilled Water up to 100.0.
TABLE IA______________________________________RESULTSORGANISM LOG REDUCTION.sup.(1)Sol. S. aureus P. aeruginosa E. coli Effec-# T = 14 T = 28 T = 14 T = 28 T = 14 T = 28 tive______________________________________ 1 6.5 5.4 6.5 5.4 6.2 5.0 Pass 2 6.5 5.4 6.5 5.4 6.2 5.0 Pass 3 6.5 5.4 6.5 5.4 6.2 5.0 Pass 4 6.5 5.4 6.5 5.4 6.2 5.0 Pass 5 6.5 5.4 6.5 5.4 6.2 5.0 Pass 6 6.5 5.4 6.5 5.4 6.2 5.0 Pass 7 6.5 5.4 6.5 5.4 6.2 5.0 Pass 8 6.5 5.4 6.5 5.4 4.7 5.0 Pass 9 6.5 5.4 6.5 5.4 4.4 5.0 Pass10 6.5 5.4 6.5 5.4 4.3 5.0 Pass11 6.5 5.4 1.5 1.9 6.2 5.0 Fail12 6.5 5.4 1.1 1.3 4.2 3.7 Fail13 6.5. 5.4 0.6 0.7 3.6 1.4 Fail14 6.5 5.4 0.6 0.3 3.3 1.6 Fail15 6.5 5.4 0.4 0.1 1.7 1.5 Fail16 6.5 5.4 0.3 0.3 1.0 1.2 Fail17 6.5 5.4 0.3 0.3 0.4 0.7 Fail18 6.5 5.4 0.1 0.3 1.0 1.6 Fail19 6.5 5.4 0.2 0.4 1.6 3.2 Fail20 6.5 5.4 0.1 0.5 1.5. 3.3 Fail______________________________________ Note: .sup.(1) 3 log reduction at 14 days and 28 days required for each test organisms.
The borate buffered PHMB solutions evaluated are effective as preserved solutions whereas the phosphate buffered solutions are not effective at the PHMB concentrations of 0.99 ppm or less.
In this example the effectiveness of polyhexamethylene biguanide hydrochloride (n=4.5 to 6.5) as a disinfecting agent is evaluated. Each disinfecting solution is prepared by the method of Example I. All ingredients are by weight percent unless otherwise noted. Following the microbial test methods of Example I, each solution is evaluated as a disinfectant against S. epidermidis, and C. albicans, and A. fumigatus organisms after 5 hours. To be considered effective in this test, there must be at least 3 log (103) reduction in the amount of S. epidermidis and no growth in C. albicans within 5 hours. The solutions and test results are tabulated in Table II below.
TABLE II__________________________________________________________________________PHMB DISINFECTING SOLUTIONSFORMULATION.sup.(1) ORGANISM LOG REDUCTIONSol. Sodium Boric Sodium Na2 Poloxamine PHMB S. epidermidis C. albicans# Chlor. Acid Borate EDTA 1107 (ppm) T = 5 Hrs..sup.(2) T = 5 Hrs..sup.(3)__________________________________________________________________________1 0.49 0.64 0.16 0.11 0.5 0.88 6.0 1.32 0.29 1.0 0.29 0.11 0.5 0.88 6.0 1.43 0.49 0.64 0.16 0.11 1.0 0.88 6.0 1.54 0.29 1.0 0.29 0.11 1.0 0.88 6.0 1.95 0.49 0.64 0.16 0.11 0.5 0.99 6.0 1.56 0.29 1.0 0.29 0.11 0.5 0.99 6.0 1.77 0.49 0.64 0.16 0.11 1.0 0.99 6.0 1.58 0.29 1.0 0.29 0.11 1.0 0.99 4.6 2.09 0.29 1.0 0.29 0.11 0.5 0.55 4.7 0.410 0.49 0.64 0.16 0.11 1.0 0.55 4.2 0.411 0.49 0.64 0.16 0.11 1.0 0.55 3.7 1.912 0.49 0.64 0.12 0.055 1.0 0.55 4.4 2.413 0.49 0.64 0.12 0.022 1.0 0.55 4.0 2.914 0.49 0.68 0.12 0.01 1.0 0.55 4.3 4.2__________________________________________________________________________ Note: .sup.(1) Distilled water qs to 100.0 .sup.(2) 3 log reduction at 5 hours required. .sup.(3) An indication of log reduction in 5 hours required.
An aqueous contact lens disinfecting solution is prepared with the following formulation:
______________________________________ Percent (w/v)______________________________________Polyhexamethylene Biguanide HCl* .00011Poloxamine 1107 .50Sodium Borate .20Boric Acid .60Sodium Chloride .49Distilled Water qs 100.0______________________________________ *n = 4.5 to 6.5.
The solution is prepared and sterilized following the procedures of Example I. Additional solutions are prepared in the same manner except the level of PHMB is 2 ppm, 3 ppm, 5 ppm, 10 ppm, or 55 ppm.
The corneal staining property of each of the above solutions is evaluated in small patient clinical groups. The eyes of each patient are examined early in the morning to establish a baseline condition. Then the solution to be evaluated is administered to the patient's eyes. The eyes are observed immediately after application of the solution, four hours later and eight hours later. The increase in corneal staining (redness) is noted for each patient. The limit for acceptable amount of increase in corneal staining is 11 percent. The results are tabulated in Table V below.
TABLE V______________________________________ Percent Corneal StainingAmount PHMB (ppm) (Average for Group)______________________________________1 72 5.53 95 1710 21.555 62Controls:Commercial Product(with thimerosal)F 35 C* 25______________________________________ *To date, this commercial product has been considered the best commercial disinfecting solution.
Table IV, in combination with Table V, demonstrates that cytotoxicity and corneal staining are relatively independent functions. A contact lens solution may be non-cytotoxic and still not be acceptable to the patient. However, a contact lens solution which is cytotoxic will definitely be unacceptable to the patient as is the case of using 100 ppm chlorhexidine and BAK in contact lens solutions. On the other hand, 10 ppm PHMB is non-cytotoxic but has an unacceptable level of ocular irritation manifested in clinically observed ocular staining of 21.5 percent. The same explanation applies to 5 ppm PHMB, 10 ppm chlorhexidine and 10 ppm BAK.
In this example, the effectiveness of polyhexamethylene biguanide hydrochloride (n=4.5 to 6.5) as a preserving agent is evaluated, using an enhanced phospate buffer system. Each preserved solution is prepared by the method of Example V and each is adjusted so as to be isotonic. All ingredients are by weight percent unless otherwise noted. Following the microbial test methods of Example I, each solution is evaluated for effectiveness against S. aureus, P. aeruginosa and E. coli organisms after 14 days and after 28 days. To be considered effective in this test, there must be at least 3 log reduction in number of organisms for each type of organism at 14 days and at 28 days. The solutions and test results are tabulated in Tables VI (formulations) and VI-A (results) below.
TABLE VI______________________________________(FORMULATIONS) SOLUTIONSIngredient 1 2 3 4 5 6 7______________________________________Polyvinyl 1.0 1.0 1.0 1.0 1.0 1.0 1.0Alcohol (98%)Hydroxypropyl- 0.20 0.36 0.10 0.30 0.30 0.30 0.30methyl CelluloseGelatin 0.10 0.10 0.10 0.10 0.10 0.10 0.10Dibasic Phosphate 0.45 0.45 0.45 0.45 0.45 0.45 0.45Monobasic Phos- 0.10 0.10 0.10 0.10 0.10 0.10 0.10phateNa2 EDTA 0.11 0.11 0.11 0.11 0.11 0.11 0.11Sodium Chlorate 0.61 0.56 0.56 0.56 0.56 0.56 0.56PHMD 1.1 1.1 1.1 1.1 1.1 1.1 1.1Poloxamine 1107 -- -- -- -- -- -- 0.10Cocoamidopropyl -- -- -- 0.10 0.10 0.10 0.10BetaineWater, qs to 100.0______________________________________
TABLE VI-A______________________________________(RESULTS)ORGANISM LOG REDUCTION.sup.(1)Solution S. aureus P. aeruginosa E. coliNo. T = 14 T = 29 T = 14 T = 28 T = 14 T = 28______________________________________1 4.7 2.9 1.4 1.3 5.9 4.92 4.8 5.2 1.6 1.3 5.9 4.93 5.0 5.2 1.6 1.2 5.9 4.94 6.2 5.1 5.7 4.6 6.0 5.05 6.2 5.1 5.7 4.8 6.0 5.06 6.2 5.1 5.7 4.8 6.0 5.07 6.2 5.1 5.7 4.8 6.0 5.0______________________________________ .sup.(1) 3 log reduction at 14 and 28 days required for each test organism.
Solutions 1-3 illustrative of compositions disclosed or suggested by related art discussed at the beginning of this application are ineffective compositions. Four and five are enhanced with a surfactant; compositions six and seven are enhanced with two surfactants according to this invention. Compositions four through seven each have organism log reduction values greater than 3 and are effective.
While the invention has been described in conjunction with specific examples thereof, this is illustrative only. Accordingly, many alternatives, modifications and variations will be apparent to those skilled in the art in light of the foregoing description and it is, therefore, intended to embrace all such alternatives, modifications and variations as to fall within the spirit and broad scope of the appended claims.
Patent Citations
Referenced by
Legal Events
Original Image

subset: commoncrawl


text:
WASHINGTON, D.C. — U.S. Rep. Nick Rahall (D-W.Va.) announced Thursday that the Town of Gilbert will receive federal funding to complete the Horsepen-Browning Fork combined water project upgrade.
"Gilbert is blessed to have public and private leaders who, in partnership, take the long view when it comes to family health. This funding is another sizeable down payment on a promise of clean water and better health for the community." said Rahall. "The object of this overall multi-million dollar effort does not end at the kitchen sink spigot. When we improve services to communities, families as well as businesses prosper. The entire area becomes more attractive for investment and future growth. As the quality of life increases for our region, we forge a stronger link with our fellow communities and strengthen the Nation's future."
The Town of Gilbert will receive a Water and Waste Disposal grant $350,000 from U.S. Department of Agriculture (USDA) Rural Development to complete the funding package to upgrade the current water systems and extend public water service to approximately 368 new customers. Previous funding awarded included two USDA Rural Development loans totaling $1,862,000 and two USDA-RD grants totaling $1,300,000. Other funding included $2,317,000 from the State of West Virginia, and $1,500,000 provided by the Appalachian Regional Commission. Total cost for the combined projects is $7,329,000.


text:
Latest Gear Live Videos
- Subscribe:
- YouTube
- iTunes High Definition
- iTunes Standard Version
Samsung I7500 Smartphone
Posted by Sheila Franklin Categories:
We guess we were correct yesterday. Samsung has announced that its first Android-powered smartphone, the I7500, will be released in Europe in June. The phone has a 3.2-inch HVGA AMOLED full touchscreen, a 7.2Mbps 3G HSDPA, a 5-megapixel cam, 8GB of internal memory and up to 32 GB of external memory. It is also packed with Google mobile services and a WiFi connectivity. No price has been announced as yet.
Read More | Digital Tech News
Palm Sells Shares to Survive
Posted by Sheila Franklin Categories: Cell Phones, Corporate News, Handhelds
How do you keep your company going in this evil recession? If you are Palm, you sell about 18 million shares of its stock. The proceeds will pay off $49 million in debts to Elevations Partners and the rest will go back to Palm, so that they can stay alive until the Pre is available in Q2. If you are considering the purchase of one, this might be a way to help the California company and get your own share of the phone.
Read More | MobileBurn
Verizon Blackberry BOGO Deal
Posted by Sheila Franklin Categories: Cell Phones, Handhelds, Hot Deals
Verizon is offering their line of Blackberrys as a super Valentine's Day gift. You can get up to three 8130 Pearls for free. A buy one get one free applies to their other models. That includes the Curve and 8703e for $79.00, the World Edition at a price of $99.99, and the Storm which will set you back $199.99. The deal is good while supplies last online, and each of them comes with a 2 year contract per phone.
Read More | Verizon
LG Arena KM900 Smartphone
Posted by Sheila Franklin Categories: Cell Phones, Corporate News, GPS, Handhelds, Wireless / WiFi
LG has announced that it will unveil its Arena KM900 smartphone at the Mobile World Congress in Barcelona that begins Feb. 11. The phone has a 3-inch WVGA touchscreen with 800x400 resolution and a 5 megapixel camera. The KM900 also has WiFi, A-GPS, and HSDPA 7.2 network support. What is most unique is its 3D touchscreen user interface with four customizable screens. No price or availability date has yet to be announced.
Read More | Crave
Virgin Mobile Helio Ocean 2 Smartphone
Posted by Sheila Franklin Categories: Cell Phones, GPS, Wireless / WiFi
Virgin Mobile has announced that their Helio Ocean 2 will launch on February 12. This model is slimmer than the first generation but still has the dual-sliding design. Aside from the QWERTY keyboard, the phone features a 2.6-inch TFT display (240x320,) 3G connectivity, GPS with Google maps, stereo Bluetooth, a media player with background mode playback and access to social networking sites. It will also have 3D gaming, a file viewer with editing and a 2MP camera. A 512MB MicroSD card is included in the $149.00 price.
Read More | Unwired View
HTC Touch Cruise Smartphone
Posted by Sheila Franklin Categories: Cameras, Cell Phones, GPS, Handhelds, Software
If you want more than basic GPS, the newly updated HTC Touch Cruise doesn't simply give navigational directions, it allows you to take a picture while their Footprints software saves your location. You can then add your comments and audio. The phone also has a one-touch interface and lets you locate services and traffic tangling. This a great phone for geocachers and those who want to convince their friends that they actually saw Mt. Denali. Look for the unlocked Touch Cruise in the spring for about $500.00 to $600.00.
Read More | HTC
Motorola MOTOSURF A310 Smartphone
Posted by Sheila Franklin Categories: Cell Phones, CES, Handhelds
One of Motorola's offerings at the CES is its MOTOSURF A310. The smartphone features a touchscreen with the company's new widget-based home screen which includes an auto-updating RSS reader. Running on Windows Mobile 6.1 Professional, it also has trackball navigation, Bluetooth 2.0 with A2DP support, a microSD card slot and a 3 mp auto-focus camera. The A3100 will start out in Asia and China, while the rest of us will have to wait until it finds its way further.
Read More | Mobileburn
Elecont Weather Software
Posted by Sheila Franklin Categories: Cell Phones, Handhelds, Hot Deals, Science, Software
Elecont has released an update for their Weather software. Available in both a Smartphone and Windows Mobile Pocket PC platform, it gives you a 10 day, worldwide forecast as well as hour-by-hour. Added to that are severe weather alert watches and warnings in case of extreme conditions or natural disasters. You can download a free trial and if you want to keep it, Elecont is offering a 30% discount for a price of only $9.95 until December 7.
Read More | Smartphone Thoughts Store
LG Insite Smartphone
Posted by Sheila Franklin Categories: Cell Phones, GPS, Handhelds, Wireless / WiFi
LG has finally come around to providing a smartphone for the U.S. market. The AT&T Insite has 3G speed, GPS, WiFi and Bluetooth 2.0, Windows Media Mobile Player 10 and a full color 3-inch LCD display that auto-rotates. Add to that streaming radio capability, Mobile Microsoft Office editing, Video ShareSM and both a QWERTY keyboard and 20-key version. With a price of $499.99, knock it down with a 2 year contract, a mail in rebate and the Insite is yours for $199.99.
Read More | AT&T
800MHz P565 Handset Coming Soon From ASUS
Posted by Aaron Zollo Categories: Cameras, Cell Phones, GPS, Handhelds
ASUS announced that they would soon be releasing a smartphone with a touch interface and a whopping 800MHz of processing goodness. ASUS is featuring a new touch interface they have named "Glide," which overlays the Windows Mobile operating system. The P565 features not only speed, but a 2.8-inch VGA touch screen with a resolution of 480 x 640. The face is what you would expect for a touchscreen device, but what you cannot see is the leather that lines the back of the device, clearly aiming it for a business environment. The P565 incorporates Windows Mobile 6.1 Professional, GPS, 256MB of flash, with 128MB DDR SDRAM, an SD slot, Blutooth, a 3 megapixel camera, and supports HSDPA 3.6Mbps, UMTS 2100, EDGE/GPRS/GSM 900/1800/1900, Class 10. No word yet on price or when it will launch, but it certainly should be a very capable device once it comes to market.
Read More | ASUSTeK
© Gear Live Inc. – User-posted content, unless source is quoted, is licensed under a Creative Commons Public Domain License. Gear Live graphics, logos, designs, page headers, button icons, videos, articles, blogs, forums, scripts and other service names are the trademarks of Gear Live Inc.


text:
Travis Reeves, superintendent for Surry County Schools, told NC Policy Watch that he had to eliminate 10.5 teacher assistant positions and 13 teaching positions this year through attrition.
Reeves said that the class size increases are also taking a big toll on teachers.
Surry County has been able to use some local and carryover funds to mitigate the cut to instructional supplies, but "we are extremely frugal at this point," said Reeves.
During the past five years, Surry County has had to eliminate more than 100 instructional positions thanks to budget cuts.
Surry County joins a growing list of school districts that have been forced to make difficult cuts as the 2013-14 school year approaches.