Ultrasound-triggered Microbubble Destruction
RS-50 合成器 TurboStart TBS195 产品介绍说明书
SynthesizerIt’s a Fact…The RS-50 allows musicians to forget about MIDI and focus on playing. It sports an all-new collection ofCD-quality sounds, cool performance features and simple direct-access buttons for selecting patches. Features include:•Affordable 61-note synthesizer with easy access to Roland’s latest sounds•Hundreds of new patches based on CD-quality waveforms•Direct-access buttons permit easy sound selection by category•Phrase/arpeggio generator and Multi Chord memory• D Beam controller for expressive realtime control •Rhythm Guide metronome with preset patterns and variationsPlaying the Demo SongsUse the following procedure to play the three demo songs:1.Press DEMO—beneath MODE—so it’s lit.e the VALUE -/+ buttons to select the songyou wish to hear.Note: If you want to listen to all of the demo songs played in order, select All Songs.3.Press ENTER to begin playback.4.Press EXIT to stop playback.5.Press EXIT again to return to Play mode.Selecting PatchesThe RS-50 has 640 patches organized in categories such as Piano, Guitar, Orchestra, etc. Use the following procedure to select and audition patches:1.Press PATCH—under MODE—so it’s lit.2.Press 0-9 to select the desired category, aslabeled beneath the buttons.e the VALUE -/+ buttons to choose a soundwithin the selected category.4. You can:•Play the keyboard•Press AUDITION, under MODE, so it’s lit, to automatically play a short sequence. PressAUDITION again to stop ing the Phrase/Arpeggio Feature The Phrase/Arpeggio feature plays musical motifs and figures based on the note(s) you hold down.1.Select a patch as previously described.2.Press PHRASE/ARPEGGIO so it’s lit.e the VALUE -/+ buttons to select a phrase orarpeggio.4.Hold down one or more notes on thekeyboard—the selected phrase or arpeggioplays.Note: A “phrase” is a musical motif that’s triggered by holding down a single note—“Phr” appears in the display as it plays. An “arpeggio” requires that more than one note be held down, and is shown as “Arp” in the display.5.Press PHRASE/ARPEGGIO so it’s not lit whenyou’re finished.Using the Chord Memory Feature Chord Memory lets you play a chord by touching a single key. You can assign all 12 notes in an octave to play different chords, and then save them as a set. (There are several chord sets already stored in the RS-50 at the factory.)1.Select a patch as previously described.2.Press CHORD MEMORY so it’s lit.3.Press a key on the keyboard to hear the chord itplays.4.Try a few keys to hear the chords they play.e the VALUE -/+ buttons to select other chordsets.6.Press CHORD MEMORY when you’re finishedso it’s no longer lit.Using the D Beam ControllerThe three buttons directly below the D Beam lens select what the D Beam does—here’s how they work. Solo Synth1.Press SOLO SYNTH so it’s lit.2.Hold down several notes on thekeyboard—notice they don’t yet sound—andthen move your hand over the D Beam. Thenotes you’re holding down play according to your hand movements.SynthesizerActive Expression1.Press ACTIVE EXP so it’s lit.2.Hold down several notes on the keyboard andmove your hand over the D Beam. The volumeof the notes you’re holding down variesaccording to your hand movements.Assignable1.Press ASSIGNABLE so it’s lit.2.Play the keyboard and move your hand over theD Beam. The currently assigned effect is heard.e the VALUE -/+ buttons to select anothereffect. This setting is automatically rememberedthe next time you turn on ASSIGNABLE.4.Press ASSIGNABLE so it’s not lit to turn off theD Beam.Using the Rhythm GuideThe Rhythm Guide provides an easy way to produce great-sounding rhythm patterns:Selecting a Rhythm Pattern1.Press PERFORM so it’s lit.2.Press RHYTHM GUIDE so it’s lit—the rhythmbegins playing.e the VALUE -/+ buttons to select variousrhythm patterns.4.Press RHYTHM GUIDE again to halt playback. Note: You can select a pattern without playing it by holding SHIFT when you press RHYTHM GUIDE. You can then press ENTER to start playback.Switching Sounds5.While the pattern is playing, press PARTSELECT so it’s lit.6.Press the RHYTHM & SFX button so it’s lit, anduse the VALUE -/+ buttons to select a rhythm kit.Changing the Tempo7.Press TAP TEMPO so it’s lit—the current tempoof the pattern is displayed in the screen.e the VALUE -/+ buttons to adjust the tempo.9.Press EXIT to return to the previous screen. Note: You can also press the TAP TEMPO button three or more times to manually tap in the desired tempo.Splitting the KeyboardEach patch on the RS-50 uses two tones called the “upper tone” and the “lower tone.” The Key Mode setting lets you determine how these two tones are played from the keyboard. Use the following procedure to split the keyboard and select sounds:1.Press PATCH so it’s lit.2.Press KEY MODE so SPLIT is lit. The uppertone now plays in the upper part of the keyboard and the lower tone plays in the lower part of thekeyboard.3.Press PARAM beneath EDIT so it’s lit.4.Press DESTINATION TONE so UPPER is lit,and then use the VALUE -/+ buttons to select atone for the upper part of the keyboard.5.Press DESTINATION TONE so LOWER is lit,and then use the VALUE -/+ buttons to select atone for the lower part of the keyboard.6.Press EXIT to return to the Patch Play screen. Note: A good example of a split patch is Pf12: RS Grand/Abs.Creating a Layered SoundLet’s set up a layer with a piano sound and a string sound:1.Press PATCH so it’s lit, and then press PIANO.2.Press KEY MODE so DUAL is lit—both theupper and lower tone play together across thewhole keyboard.3.Press PARAM under EDIT so it’s lit.4.Press DESTINATION TONE so UPPER is lit,and then use the VALUE -/+ buttons to select apiano tone.5.Press DESTINATION TONE so LOWER is lit,and then use the VALUE -/+ buttons to select astring tone.6.Press EXIT to return to the Patch Play screen. Note: A good example of a layered sound is Pf13: RS Grand&Pad.。
超声ultrasonic(ultrasound)声音是与人类生活紧密相联的一种自然现象
超声ultrasonic(ultrasound)声音是与人类生活紧密相联的一种自然现象。
当声的频率高到超过人耳听觉的频率极限(根据大量调查，取整数20000赫)时，人们就觉察不出声的存在，因而称这种高频率的声为“超”声。
超声波的特点束射特性由于超声波的波长短，超声波射线可以和光线一样，能够反射、折射，也能聚焦，而且．遵守几何光学上的定律。
即超声波射线从一种物质表面反射时，入射角等于反射角，当射线透过一种物质进入另一种密度不同的物质时就会产生折射，也就是要改变它的传插方向，两种物质的密度差别愈大，则折射也愈大。
吸收特性声波在各种物质中传播时，随着传播距离的增加，强度会渐进减弱，这是因为物质要吸收掉它的能量。
对于同一物质，声波的频率越高，吸收越强。
对于一个频率一定的声波，在气体中传播时吸收最历害，在液体中传播时吸收比较弱，在固体中传播时吸收最小。
超声波的能量传递特性超声波所以往各个工业部门中有广泛的应用，主要之点还在于比声波具有强大得多的功率。
为什么有强大的功率呢?因为当声波到达某一物资中时，由于声波的作用使物质中的分子也跟着振动，振动的频率和声波频率—样，分子振动的频率决定了分子振动的速度。
频率愈高速度愈大。
物资分子由于振动所获得的能量除了与分子的质量有关外，是由分子的振动速度的平方决定的,所以如果声波的频率愈高，也就是物质分子愈能得到更高的能量、超声波的频率比声波可以高很多，所以它可以使物资分子获得很大的能量；换句话说，超声波本身可以供给物质足够大的功率。
超声波的声压特性当声波通入某物体时,由于声波振动使物质分子产生压缩和稀疏的作用，将使物质所受的压力产生变化。
由于声波振动引起附加压力现象叫声压作用。
由于超声波所具有的能量很大，就有可能使物质分子产生显诸的声压作用、例如当水中通过一般强度的超声波时，产生的附加压力可以达到好几个大气压力。
液体中存起着如此巨大的声压作用，就会引起值得注意的现象。
当超声波振动使液体分子压缩时，好象分子受到来直四面八方的压力；当超声波振动使液体分子稀疏时，好象受到向外散开的拉力，对于液体，它们比较受得住附加压力的作用，所以在受到压缩力的时候；不大会产生反常情形。
超低功耗微型超声时间差测距传感器CH101说明书
CH101 Ultra-low Power Integrated Ultrasonic Time-of-Flight Range SensorChirp Microsystems reserves the right to change specifications and information herein without notice.Chirp Microsystems2560 Ninth Street, Ste 200, Berkeley, CA 94710 U.S.A+1(510) 640–8155Document Number: DS-000331Revision: 1.2Release Date: 07/17/2020CH101 HIGHLIGHTSThe CH101 is a miniature, ultra-low-power ultrasonic Time-of-Flight (ToF) range sensor. Based on Chirp’s patented MEMS technology, the CH101 is a system-in-package that integrates a PMUT (Piezoelectric Micromachined Ultrasonic Transducer) together with an ultra-low-power SoC (system on chip) in a miniature, reflowable package. The SoC runs Chirp’s advanced ultrasonic DSP algorithms and includes an integrated microcontroller that provides digital range readings via I2C.Complementing Chirp’s long-range CH201 ultrasonic ToF sensor product, the CH101 provides accurate range measurements to targets at distances up to 1.2m. Using ultrasonic measurements, the sensor works in any lighting condition, including full sunlight to complete darkness, and provides millimeter-accurate range measurements independent of the target’s color and optical transparency. The sensor’s Field-of-View (FoV) can be customized and enables simultaneous range measurements to multiple objects in the FoV. Many algorithms can further process the range information for a variety of usage cases in a wide range of applications.The CH101-00ABR is a Pulse-Echo product intended for range finding and presence applications using a single sensor for transmit and receive of ultrasonic pulses. The CH101-02ABR is a frequency matched Pitch-Catch product intended for applications using one sensor for transmit and a second sensor for receiving the frequency matched ultrasonic pulse.DEVICE INFORMATIONPART NUMBER OPERATION PACKAGECH101-00ABR Pulse-Echo 3.5 x 3.5 x 1.26mm LGA CH101-02ABR Pitch-Catch 3.5 x 3.5 x 1.26mm LGA RoHS and Green-Compliant Package APPLICATIONS•Augmented and Virtual Reality•Robotics•Obstacle avoidance•Mobile and Computing Devices•Proximity/Presence sensing•Ultra-low power remote presence-sensing nodes •Home/Building automation FEATURES•Fast, accurate range-finding•Operating range from 4 cm to 1.2m•Sample rate up to 100 samples/sec• 1.0 mm RMS range noise at 30 cm range•Programmable modes optimized for medium and short-range sensing applications•Customizable field of view (FoV) up to 180°•Multi-object detection•Works in any lighting condition, including full sunlight to complete darkness•Insensitive to object color, detects opticallytransparent surfaces (glass, clear plastics, etc.) •Easy to integrate•Single sensor for receive and transmit•Single 1.8V supply•I2C Fast-Mode compatible interface, data rates up to 400 kbps•Dedicated programmable range interrupt pin•Platform-independent software driver enables turnkey range-finding•Miniature integrated module• 3.5 mmx 3.5 mm x 1.26 mm, 8-pin LGA package•Compatible with standard SMD reflow•Low-power SoC running advanced ultrasound firmware•Operating temperature range: -40°C to 85°C •Ultra-low supply current• 1 sample/s:o13 µA (10 cm max range)o15 µA (1.0 m max range)•30 samples/s:o20 µA (10 cm max range)o50 µA (1.0 m max range)Table of ContentsCH101 Highlights (1)Device Information (1)Applications (1)Features (1)Simplified Block Diagram (3)Absolute Maximum Ratings (4)Package Information (5)8-Pin LGA (5)Pin Configuration (5)Pin Descriptions (6)Package Dimensions (6)Electrical Characteristics (7)Electrical Characteristics (Cont’d) (8)Typical Operating Characteristics (9)Detailed Description (10)Theory of Operation (10)Device Configuration (10)Applications (11)Chirp CH101 Driver (11)Object Detection (11)Interfacing to the CH101 Ultrasonic Sensor (11)Device Modes of Operation: (12)Layout Recommendations: (13)PCB Reflow Recommendations: (14)Use of Level Shifters (14)Typical Operating Circuits (15)Ordering Information (16)Part Number Designation (16)Package Marking (17)Tape & Reel Specification (17)Shipping Label (17)Revision History (19)SIMPLIFIED BLOCK DIAGRAMFigure 1. Simplified Block DiagramABSOLUTE MAXIMUM RATINGSPARAMETER MIN. TYP. MAX. UNIT AVDD to VSS -0.3 2.2 V VDD to VSS -0.3 2.2 V SDA, SCL, PROG, RST_N to VSS -0.3 2.2 V Electrostatic Discharge (ESD)Human Body Model (HBM)(1)Charge Device Model (CDM)(2)-2-5002500kVV Latchup -100 100 mA Temperature, Operating -40 85 °C Relative Humidity, Storage 90 %RH Continuous Input Current (Any Pin) -20 20 mA Soldering Temperature (reflow) 260 °CTable 1. Absolute Maximum RatingsNotes:1.HBM Tests conducted in compliance with ANSI/ESDA/JEDEC JS-001-2014 Or JESD22-A114E2.CDM Tests conducted in compliance with JESD22-C101PACKAGE INFORMATION8-PIN LGADESCRIPTION DOCUMENT NUMBER CH101 Mechanical Integration Guide AN-000158CH101 and CH201 Ultrasonic Transceiver Handling andAssembly Guidelines AN-000159Table 2. 8-Pin LGAPIN CONFIGURATIONTop ViewFigure 2. Pin Configuration (Top View)PIN DESCRIPTIONSPIN NAME DESCRIPTION1 INT Interrupt output. Can be switched to input for triggering and calibration functions2 SCL SCL Input. I2C clock input. This pin must be pulled up externally.3 SDA SDA Input/Output. I2C data I/O. This pin must be pulled up externally.4 PROG Program Enable. Cannot be floating.5 VSS Power return.6 VDD Digital Logic Supply. Connect to externally regulated 1.8V supply. Suggest commonconnection to AVDD. If not connected locally to AVDD, b ypass with a 0.1μF capacitor asclose as possible to VDD I/O pad.7 AVDD Analog Power Supply. Connect to externally re gulated supply. Bypass with a 0.1μFcapacitor as close as possible to AVDD I/O pad.8 RESET_N Active-low reset. Cannot be floating.Table 3. Pin DescriptionsPACKAGE DIMENSIONSFigure 3. Package DimensionsELECTRICAL CHARACTERISTICSAVDD = VDD = 1.8VDC, VSS = 0V, T A = +25°C, min/max are from T A = -40°C to +85°C, unless otherwise specified.PARAMETER SYMBOL CONDITIONS MIN TYP MAX UNITSPOWER SUPPLYAnalog Power Supply AVDD 1.62 1.8 1.98 V Digital Power Supply VDD 1.62 1.8 1.98 VULTRASONIC TRANSMIT CHANNELOperating Frequency 175 kHzTXRX OPERATION (GPR FIRMWARE USED UNLESS OTHERWISE SPECIFIED)Maximum Range Max Range Wall Target58 mm Diameter Post1.2(1)0.7mm Minimum Range Min Range Short-Range F/W used 4(2)cm Measuring Rate (Sample/sec) SR 100 S/s Field of View FoV Configurable up to 180º deg Current Consumption (AVDD +VDD) I SSR=1S/s, Range=10 cmSR=1S/s, Range=1.0mSR=30S/s, Range=10 cmSR=30S/s, Range=1.0m13152050μAμAμAμA Range Noise N R Target range = 30 cm 1.0 mm, rms Measurement Time 1m max range 18 ms Programming Time 60 msTable 4. Electrical CharacteristicsNotes:1.Tested with a stationary target.2.For non-stationary objects. While objects closer than 4cm can be detected, the range measurement is not ensured.ELECTRICAL CHARACTERISTICS (CONT’D)AVDD = VDD = 1.8VDC, VSS = 0V, T A = +25°C, unless otherwise specified.PARAMETERSYMBOL CONDITIONS MINTYP MAX UNITS DIGITAL I/O CHARACTERISTICS Output Low Voltage V OL SDA, INT,0.4 V Output High Voltage V OH INT 0.9*V VDD V I 2C Input Voltage Low V IL_I2C SDA, SCL 0.3*V VDDV I 2C Input Voltage High V IH_I2C SDA, SCL 0.7*V VDD V Pin Leakage Current I L SDA,SCL, INT(Inactive), T A =25°C±1μA DIGITAL/I 2C TIMING CHARACTERISTICSSCL Clock Frequencyf SCLI 2C Fast Mode400kHzTable 5. Electrical Characteristics (Cont’d)TYPICAL OPERATING CHARACTERISTICSAVDD = VDD = 1.8VDC, VSS = 0V, T A = +25°C, unless otherwise specified.Typical Beam Pattern – MOD_CH101-03-01 Omnidirectional FoV module(Measured with a 1m2 flat plate target at a 30 cm range)Figure 4. Beam pattern measurements of CH101 moduleDETAILED DESCRIPTIONTHEORY OF OPERATIONThe CH101 is an autonomous, digital output ultrasonic rangefinder. The Simplified Block Diagram, previously shown, details the main components at the package-level. Inside the package are a piezoelectric micro-machined ultrasonic transducer (PMUT) and system-on-chip (SoC). The SoC controls the PMUT to produce pulses of ultrasound that reflect off targets in the sensor’s Field of View (FoV). The reflections are received by the same PMUT after a short time delay, amplified by sensitive electronics, digitized, and further processed to produce the range to the primary target. Many algorithms can further process the range information for a variety of usage cases in a wide range of applications.The time it takes the ultrasound pulse to propagate from the PMUT to the target and back is called the time-of-flight (ToF). The distance to the target is found by multiplying the time-of-flight by the speed of sound and dividing by two (to account for the round-trip). The speed of sound in air is approximately 343 m/s. The speed of sound is not a constant but is generally stable enough to give measurement accuracies within a few percent error.DEVICE CONFIGURATIONA CH101 program file must be loaded into the on-chip memory at initial power-on. The program, or firmware, is loaded through a special I2C interface. Chirp provides a default general-purpose rangefinder (GPR) firmware that is suitable for a wide range of applications. This firmware enables autonomous range finding operation of the CH101. It also supports hardware-triggering of the CH101 for applications requiring multiple transceivers. Program files can also be tailored to the customer’s application. Contact Chirp for more information.CH101 has several features that allow for low power operation. An ultra-low-power, on-chip real-time clock (RTC) sets the sample rate and provides the reference for the time-of-flight measurement. The host processor does not need to provide any stimulus to the CH101 during normal operation, allowing the host processor to be shut down into its lowest power mode until the CH101 generates a wake-up interrupt. There is also a general-purpose input/output (INT) pin that is optimized to be used as a system wake-up source. The interrupt pin can be configured to trigger on motion or proximity.APPLICATIONSCHIRP CH101 DRIVERChirp provides a compiler and microcontroller-independent C driver for the CH101 which greatly simplifies integration. The CH101 driver implements high-level control of one or more CH101s attached to one or more I2C ports on the host processor. The CH101 driver allows the user to program, configure, trigger, and readout data from the CH101 through use of C function calls without direct interaction with the CH101 I2C registers. The CH101 driver only requires the customer to implement an I/O layer which communicates with the host processor’s I2C hardware and GPIO hardware. Chirp highly recommends that all designs use the CH101 driver.OBJECT DETECTIONDetecting the presence of objects or people can be optimized via software, by setting the sensor’s full-scale range (FSR), and via hardware, using an acoustic housing to narrow or widen the sensor’s field-of-view. The former means that the user may set the maximum distance at which the sensor will detect an object. FSR values refer to the one-way distance to a detected object.In practice, the FSR setting controls the amount of time that the sensor spends in the listening (receiving) period during a measurement cycle. Therefore, the FSR setting affects the time required to complete a measurement. Longer full-scale range values will require more time for a measurement to complete.Ultrasonic signal processing using the CH101’s General Purpose Rangefinder (GPR) Firmware will detect echoes that bounce off the first target in the Field-of-View. The size, position, and material composition of the target will affect the maximum range at which the sensor can detect the target. Large targets, such as walls, are much easier to detect than smaller targets. Thus, the associated operating range for smaller targets will be shorter. The range to detect people will be affected by a variety of factors such as a person’s size, clothing, orientation to the sensor and the sensor’s field-of-view. In general, given these factors, people can be detected at a maximum distance of 0.7m from the CH101 sensor.For additional guidance on the detection of people/objects using the NEMA standard, AN-000214 Presence Detection Application Note discusses the analysis of presence detection using the Long-Range CH201 Ultrasonic sensor.INTERFACING TO THE CH101 ULTRASONIC SENSORThe CH101 communicates with a host processor over the 2-wire I2C protocol. The CH101 operates as an I2C slave and responds to commands issued by the I2C master.The CH101 contains two separate I2C interfaces, running on two separate slave addresses. The first is for loading firmware into the on-chip program memory, and the second is for in-application communication with the CH101. The 7-bit programming address is0x45, and the 7-bit application address default is 0x29. The application address can be reprogrammed to any valid 7-bit I2C address. The CH101 uses clock stretching to allow for enough time to respond to the I2C master. The CH101 clock stretches before the acknowledge (ACK) bit on both transmit and receive. For example, when the CH101 transmits, it will hold SCL low after it transmits the 8th bit from the current byte while it loads the next byte into its internal transmit buffer. When the next byte is ready, it releases the SCL line, reads the master’s ACK bit, and proceeds accordingly. When the CH101 is receiving, it holds the SCL line low after it receives the 8th bit in a byte. The CH101 then chooses whether to ACK or NACK depending on the received data and releases the SCL line.The figure below shows an overview of the I2C slave interface. In the diagram, ‘S’ indicates I2C start, ‘R/W’ is the read/write bit, ‘Sr’ is a repeated start, ‘A’ is acknowledge, and ‘P’ is the stop condition. Grey boxes indicate the I2C master actions; white boxes indicate the I2C slave actions.Figure 5. CH101 I2C Slave Interface DiagramDEVICE MODES OF OPERATION:FREE-RUNNING MODEIn the free-running measurement mode, the CH101 runs autonomously at a user specified sample rate. In this mode, the INT pin is configured as an output. The CH101 pulses the INT pin high when a new range sample is available. At this point, the host processor may read the sample data from the CH101 over the I2C interface.HARDWARE-TRIGGERED MODEIn the hardware triggered mode, the INT pin is used bi-directionally. The CH101 remains in an idle condition until triggered by pulsing the INT pin. The measurement will start with deterministic latency relative to the rising edge on INT. This mode is most useful for synchronizing several CH101 transceivers. The host controller can use the individual INT pins of several transceivers to coordinate the exact timing.CH101 BEAM PATTERNSThe acoustic Field of View is easily customizable for the CH101 and is achieved by adding an acoustic housing to the transceiver that is profiled to realize the desired beam pattern. Symmetric, asymmetric, and omnidirectional (180° FoV) beam patterns are realizable. An example beam pattern is shown in the Typical Operating Characteristics section of this document and several acoustic housing designs for various FoV’s are available from Chirp.LAYOUT RECOMMENDATIONS:RECOMMENDED PCB FOOTPRINTDimensions in mmFigure 6. Recommended PCB FootprintPCB REFLOW RECOMMENDATIONS:See App Note AN-000159, CH101 and CH201 Ultrasonic Transceiver Handling and Assembly Guidelines.USE OF LEVEL SHIFTERSWhile the use of autosense level shifters for all the digital I/O signal signals is acceptable, special handling of the INT line while using a level shifter is required to ensure proper resetting of this line. As the circuit stage is neither a push-pull nor open-drain configuration (see representative circuit below), it is recommended that level shifter with a manual direction control line be used. The TI SN74LVC2T45 Bus Transceiver is a recommended device for level shifting of the INT signal line.Figure 7. INT Line I/O Circuit StageTYPICAL OPERATING CIRCUITSFigure 8. Single Transceiver OperationFigure 9. Multi- Transceiver OperationORDERING INFORMATIONPART NUMBER DESIGNATIONFigure 10. Part Number DesignationThis datasheet specifies the following part numbersPART NUMBER OPERATION PACKAGE BODY QUANTITY PACKAGING CH101-00ABR Pulse-Echo 3.5 mm x 3.5 mm x 1.26 mmLGA-8L 1,000 7” Tape and ReelCH101-02ABR Pitch-Catch 3.5 mm x 3.5 mm x 1.26 mmLGA-8L 1,000 7” Tape and ReelTable 6. Part Number DesignationCH101-xxABxProduct FamilyProduct Variant Shipping CarrierR = Tape & Reel 00AB = Pulse-Echo Product Variant02AB = Pitch-Catch Product VariantCH101 = Ultrasonic ToF SensorPACKAGE MARKINGFigure 11. Package MarkingTAPE & REEL SPECIFICATIONFigure 12. Tape & Reel SpecificationSHIPPING LABELA Shipping Label will be attached to the reel, bag and box. The information provided on the label is as follows:•Device: This is the full part number•Lot Number: Chirp manufacturing lot number•Date Code: Date the lot was sealed in the moisture proof bag•Quantity: Number of components on the reel•2D Barcode: Contains Lot No., quantity and reel/bag/box numberDimensions in mmDEVICE: CH101-XXXXX-XLOT NO: XXXXXXXXDATE CODE: XXXXQTY: XXXXFigure 13. Shipping LabelREVISION HISTORY09/30/19 1.0 Initial Release10/22/19 1.1 Changed CH-101 to CH101. Updated figure 7 to current markings.07/17/20 1.2 Format Update. Incorporated “Maximum Ratings Table” and “Use of LevelShifters” section.This information furnished by Chirp Microsystems, Inc. (“Chirp Microsystems”) is believed to be accurate and reliable. However, no responsibility is assumed by Chirp Microsystems for its use, or for any infringements of patents or other rights of third parties that may result from its use. Specifications are subject to change without notice. Chirp Microsystems reserves the right to make changes to this product, including its circuits and software, in order to improve its design and/or performance, without prior notice. Chirp Microsystems makes no warranties, neither expressed nor implied, regarding the information and specifications contained in this document. Chirp Microsystems assumes no responsibility for any claims or damages arising from information contained in this document, or from the use of products and services detailed therein. This includes, but is not limited to, claims or damages based on the infringement of patents, copyrights, mask work and/or other intellectual property rights.Certain intellectual property owned by Chirp Microsystems and described in this document is patent protected. No license is granted by implication or otherwise under any patent or patent rights of Chirp Microsystems. This publication supersedes and replaces all information previously supplied. Trademarks that are registered trademarks are the property of their respective companies. Chirp Microsystems sensors should not be used or sold in the development, storage, production or utilization of any conventional or mass-destructive weapons or for any other weapons or life threatening applications, as well as in any other life critical applications such as medical equipment, transportation, aerospace and nuclear instruments, undersea equipment, power plant equipment, disaster prevention and crime prevention equipment.©2020 Chirp Microsystems. All rights reserved. Chirp Microsystems and the Chirp Microsystems logo are trademarks of Chirp Microsystems, Inc. The TDK logo is a trademark of TDK Corporation. Other company and product names may be trademarks of the respective companies with which they are associated.©2020 Chirp Microsystems. All rights reserved.。
超声造影剂Sonazoid（示卓安）用于肝脏疾病进展
Application progresses of ultrasound contrast agentSonazoid in liver diseasesZHANG Zheyuan， ZHANG Huabin， BAI Zhiyong*（Department of Ultrasound， Beijing Tsinghua Changgung Hospital， School ofClinical Medicine， Tsinghua University， Beijing 102218， China）［Abstract］With the rapid development of contrast-enhanced ultrasound （CEUS），Sonazoid，a new generation of ultrasound microbubbles contrast agent came into being.The unique Kupffer phase of Sonazoid could greatly prolong the intrahepatic developing time，hence providing more valuable information for diagnosis，treatment and follow-up of liver diseases. The progresses of Sonazoid applicated in liver diseases were reviewed in this article.［Keywords］liver； contrast media； ultrasonographyDOI：10.13929/j.issn.1672-8475.2024.02.010超声造影剂Sonazoid（示卓安）用于肝脏疾病进展张哲元，张华斌，白志勇*（清华大学附属北京清华长庚医院超声科清华大学临床医学院，北京 102218）［摘要］随着超声造影技术迅速发展，新一代超声微泡造影剂——Sonazoid（示卓安）应运而生，其特有的Kupffer相可极大地延长肝内显影时间，为诊断、治疗及随访肝脏疾病提供更多有价值的信息。
211126668_超声波辅助酶法提取牛皮胶原蛋白及其结构表征
赵改名，王壮壮，祝超智，等. 超声波辅助酶法提取牛皮胶原蛋白及其结构表征[J]. 食品工业科技，2023，44（9）：190−199. doi:10.13386/j.issn1002-0306.2022070219ZHAO Gaiming, WANG Zhuangzhuang, ZHU Chaozhi, et al. Ultrasound-Assisted Enzymatic Extraction and Structural Characterization of Cowhide Collagen[J]. Science and Technology of Food Industry, 2023, 44(9): 190−199. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2022070219· 工艺技术 ·超声波辅助酶法提取牛皮胶原蛋白及其结构表征赵改名1，王壮壮1，祝超智1, *，余小领1，张秋会1，祁兴山2（1.河南农业大学食品科学技术学院，河南郑州 450002；2.恒都综合试验站，河南驻马店 463000）摘 要：以牛皮为原料，优化超声波辅助酶提取牛皮中胶原蛋白的工艺。
在单因素实验的基础上设计响应面试验，以牛皮胶原蛋白提取率为响应值，优化得到胶原蛋白的最佳提取工艺，并对其进行结构表征。
结果表明：牛皮中胶原蛋白的最佳提取工艺条件为超声波功率161 W 、超声波处理时间64 min 、胃蛋白酶添加量109 U/g 、料液比1:16 g/mL ，在此条件下胶原蛋白的提取率为63.77%。
十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE ）、紫外光谱（UV ）和傅立叶红外光谱（FTIR ）分析表明，超声波辅助酶提取的胶原蛋白符合Ⅰ型胶原蛋白的特征，保持了其完整的三螺旋结构，氨基酸组成和扫描电镜（SEM ）分析得到超声波辅助酶提取的胶原蛋白三螺旋稳定程度略微下降。
超声波的作用与功效的英语作文350字
全文分为作者个人简介和正文两个部分：作者个人简介：Hello everyone, I am an author dedicated to creating and sharing high-quality document templates. In this era of information overload, accurate and efficient communication has become especially important. I firmly believe that good communication can build bridges between people, playing an indispensable role in academia, career, and daily life. Therefore, I decided to invest my knowledge and skills into creating valuable documents to help people find inspiration and direction when needed.正文：超声波的作用与功效的英语作文350字全文共3篇示例，供读者参考篇1The Myriad Applications of Ultrasound WavesUltrasound, the acronym for ultrasonic sound waves, refers to acoustic vibrations with frequencies beyond the upper audible limit of human hearing, typically above 20,000 Hz. While thesehigh-pitched sound waves may be imperceptible to our ears, their diverse applications span numerous fields, making ultrasound a truly remarkable technological marvel.In the medical realm, ultrasound imaging, also known as sonography, has revolutionized diagnostic procedures. By utilizing high-frequency sound waves and their echoes, doctors can create detailed images of internal organs, muscles, and other structures within the body. This non-invasive technique is particularly invaluable in monitoring fetal development during pregnancy, enabling expectant mothers to catch glimpses of their unborn babies.However, ultrasound's utility extends far beyond medical diagnostics. It finds widespread use in industrial settings for tasks such as nondestructive testing (NDT) and material characterization. Engineers can employ ultrasonic waves to detect flaws, cracks, or defects in various materials, ensuring the structural integrity and safety of components without causing damage.Moreover, ultrasound has proven its efficacy in the field of cleaning and surface treatment. Ultrasonic cleaners harness the power of cavitation, a phenomenon where alternating high and low-pressure waves create millions of microscopic bubbles thatimplode, effectively removing contaminants from intricate and hard-to-reach areas. This process is particularly useful for cleaning delicate items like jewelry, optical components, and precision instruments.Interestingly, ultrasound has even found applications in the culinary world. Certain techniques, such as ultrasonic mixing and emulsification, can enhance the flavor and texture of various foods and beverages. Additionally, ultrasonic waves have been explored for potential use in food preservation, offering an alternative to traditional methods like thermal processing or chemical treatments.Despite its widespread adoption, research into ultrasound continues to unveil new and exciting possibilities. From novel medical therapies to advanced materials processing, the potential of these high-frequency sound waves remains boundless, and their impact on our lives is only set to grow in the years to come.篇2The Magic of Ultrasound: Unveiling Its Incredible Uses and EffectsAs a student fascinated by the marvels of science and technology, I have been captivated by the remarkable phenomenon of ultrasound. This invisible force, operating at frequencies beyond the human audible range, has proven to be a game-changer in various fields, revolutionizing the way we perceive and interact with the world around us.One of the most well-known applications of ultrasound is in the field of medical imaging. Ultrasound technology has become an indispensable tool in diagnostics, allowing healthcare professionals to peer into the depths of the human body without invasive procedures. Through the use of high-frequency sound waves, detailed images of internal organs, tissues, and even fetuses can be obtained, aiding in early detection and treatment of various conditions.However, the wonders of ultrasound extend far beyond medical imaging. Its versatility has found applications in diverse industries, ranging from manufacturing to environmental conservation. In manufacturing, ultrasonic welding and cleaning processes have streamlined production lines, ensuring precise and efficient operations. Meanwhile, in the realm of environmental protection, ultrasound has proven invaluable in monitoring and mitigating the impact of human activities onmarine life, enabling researchers to study the behavior and migration patterns of whales and other aquatic creatures without causing disturbance.But perhaps one of the most intriguing applications of ultrasound lies in its therapeutic potential. Emerging research has highlighted the promising use of focused ultrasound in treating various medical conditions, such as Parkinson's disease, essential tremor, and even certain types of cancer. By precisely targeting specific areas within the body, ultrasound waves can disrupt or destroy pathological tissues, offering a non-invasive alternative to traditional surgical interventions.As I delve deeper into the study of ultrasound, I am continually amazed by the boundless possibilities it presents. From its ability to detect microscopic flaws in materials to its potential in enhancing drug delivery systems, the applications of ultrasound seem limitless. As a student, I am inspired by the ongoing research and innovations in this field, and I eagerly anticipate the future breakthroughs that will undoubtedly shape our understanding and utilization of this incredible technology.In conclusion, ultrasound is a truly remarkable force that has revolutionized various aspects of our lives. Its versatility, precision, and non-invasive nature have made it anindispensable tool in a wide range of fields, from medicine to manufacturing and environmental conservation. As a student, I am in awe of the vast potential of ultrasound and the endless possibilities it holds for shaping a better future for humanity.篇3The Wondrous World of UltrasoundAs students, we've all had experiences with ultrasound technology, even if we didn't realize it at the time. That grainy, black and white image of a tiny being inside the womb – that's ultrasound at work! But ultrasound has so many more amazing applications beyond just peeking at unborn babies.At its core, ultrasound involves high-frequency sound waves that are inaudible to the human ear. These waves can travel through solid objects and fluids, and their echoes can be used to create detailed images. This imaging capability is what makes ultrasound so incredibly useful in the medical field.One of the most common uses of ultrasound is in diagnosing various conditions. Doctors can use ultrasound to examine organs like the heart, liver, and kidneys for any abnormalities or irregularities. It's also invaluable in monitoring the growth and development of fetuses during pregnancy.Unlike X-rays, ultrasound doesn't involve any harmful radiation, making it a safe and non-invasive diagnostic tool.But ultrasound isn't just about imaging – it can also be used for therapeutic purposes. High-intensity focused ultrasound (HIFU) is a cutting-edge technology that can be used to treat certain types of cancers and other conditions. The ultrasound waves are concentrated on a specific area, heating and destroying targeted tissues without harming surrounding healthy cells.Ultrasound even has applications beyond the medical realm. It's used in industries like manufacturing for tasks like flaw detection and quality control. Marine biologists use it to study the behavior and habitats of underwater creatures. And who could forget those fancy ultrasonic jewelry cleaners that use ultrasound waves to dislodge dirt and grime from intricate pieces?As technology continues to advance, the potential uses of ultrasound are only going to grow. From improving surgical precision to developing new cleaning methods, the possibilities are truly exciting. So the next time you see those grainy ultrasound images, remember – they're just the tip of the iceberg when it comes to this remarkable technology!。
Ultrasound-promoted intramolecular direct arylation in a capillary flow microreactor
Ultrasound-promoted intramolecular direct arylation in a capillary flow microreactorLei Zhang,Mei Geng,Peng Teng,Dan Zhao,Xi Lu,Jian-Xin Li ⇑State Key Lab of Analytical Chemistry for Life Science,School of Chemistry and Chemical Engineering,Nanjing University,Nanjing 210093,PR Chinaa r t i c l e i n f o Article history:Received 23March 2011Accepted 20July 2011Available online 26July 2011Keywords:Direct arylationUltrasound irradiation MicroreactorPalladium-catalyzed Synthesisa b s t r a c tAn intramolecular direct arylation of various aryl bromides was performed using ultrasonic irradiation and a continuous flow capillary microreactor.The present procedure provided a higher functional group tolerance,ligand-free,milder reaction conditions and a shorter reaction time for the direct arylation com-pared with the conventional methods.The ultrasonic irritation not only greatly promoted the conversion and selectivity of the direct arylation,but also solved the clogging problem of the microreactor for solid-forming reaction and made the reaction run smoothly.Ó2011Elsevier B.V.All rights reserved.1.IntroductionBiaryl structural motif is observed in a variety of compounds,from natural bioactive products such as vancomycin and schizan-drin [1,2]to some important synthetic compounds like BINOL and BINAP [3,4].An arsenal of well-know catalytic methods includ-ing the Suzuki–Miyaura,Negishi and Stille couplings has been developed to build aryl-aryl bonds [5],however,all these important reactions require the preparation of pre-activated orga-nometallic reagents such as boronic acids,organo-magnesium,-tin or -zinc derivatives that always associated with additional reaction steps,wastes,solvents,purifications and time.Direct arylation as a greener and effective alternative to these commonly employed cross-coupling reactions has attracted considerable interest in re-cent years [6,7],in which the aryl–heteroaryl or aryl–aryl bonds formation of heteroaromatic compounds and simple electron-rich arenes such as pyrroles,indoles,thiophenes and phenols with aryl halides has significantly been developed [6,8–10].However,in spite of their advantages,these reactions usually need complex catalyst systems (complex ligands)and additives (e.g.silver salts),or often suffer from drawbacks such as longer reaction times,high-er temperatures (120–150°C)that significantly limit their scope and functional group tolerance [11–13].So there is still a need for general protocols on the construction of aryl–aryl bonds with a high yield,excellent selectivity and high functional group toler-ance under mild reaction conditions.Microreactor technology has received a great deal of attention for years.It has been shown to afford numerous advantages over traditional stirred-batch reactors,such as increased surface-to-vol-ume ratios,excellent mass-and heat-transfer capabilities,better reaction yields and so on,all of which would be expected to promote highly effective chemical reactions [14–16].However,one main drawback of microreactors is a clogging problem of the small reactor channels when solid-forming reactions are per-formed [17].The easy solution to this problem is highly desirable.It is well known that ultrasound irradiation has been recognized as an efficient technique in organic synthesis to accelerate the reac-tion,improve yield,shorten reaction time and increase selectivity [18–20].As part of our continuing work directed toward developing rea-sonable reaction conditions for aryl–aryl bond formation that are environmentally benign and efficient [21],a methodology study on palladium-catalyzed intramolecular direct arylation reactions using a continuous flow capillary microreactor under ultrasound irradiation was performed.Herein,we report a ligand-free and effi-cient procedure for the intramolecular direct arylation of aryl bro-mides under ultrasonic irradiation and mild conditions in the capillary microreactor.The current reactions possessed a broad substrate scope and high functional group tolerance in good to excellent yields.Furthermore,ultrasonic irradiation solved the clogging problem in microreactor.The microreactor was assem-bled simply from syringes,a conventional capillary,a mixing unit,syringe pumps and a ultrasonic cleaner,all of which are cheap and commercially available (Fig.1).2.Results and discussionIn order to obtain appropriate reaction conditions,an optimi-zation of the reaction conditions was conducted using a batch1350-4177/$-see front matter Ó2011Elsevier B.V.All rights reserved.doi:10.1016/j.ultsonch.2011.07.008Corresponding author.Tel./fax:+862583686419.E-mail address:lijxnju@ (J.-X.Li).reactor.It is reported that N,N-dimethylacetamide (DMA)is supe-rior to other solvents such as N,N-dimethylformamide (DMF),tol-uene,dioxanes and acetonitrile for direct arylation reactions [11,13,22],therefore,as an initial screen,reactions of 2-iodoben-zyl phenyl ether (1)as a substrate with 5mol%Pd(OAc)2and two equiv.of different bases were performed under nitrogen atmo-sphere at 100°C for 24h (Table 1).In pure DMA and inorganic base such as K 2CO 3,Cs 2CO 3and KOAc,substrate 1provided intra-molecular coupling product 20a ,however,both conversions and selectivity (ratio of 20a versus deiodination product 20b )were poor.While organic bases such as 4-dimethylamiopryidine (DMAP)and 1,4-diazabicyclo[2.2.2]octane (DABCO)were ineffec-tive.When a co-solvents (DMA:water)was employed for the reactions,the conversion was greatly increased.For the bases,K 2CO 3and Cs 2CO 3gave an improved conversion,while,NaOAc gave an inferior result.Meaningfully,in the present of KOAc and a 10:1mixture of DMA and water,the conversion was in-creased up to 90%,however,the reaction selectivity was almost unchanged (Table 1,entry 1vs.6,2vs.7,and 5vs.9).Fortu-nately,with changing the substrate 1to 2-bromobenzyl phenyl ether (2),the selectivity was improved more than twice,from 14:1to 32:1(Table 1,entry 9and 10),however,the conversion became to be in a moderate level.In order to optimize the ratio of DMA and water,the effects ofresulted in a lower conversion.It might be reasoned that by per-forming the reaction in the presence of water,the solubility of the inorganic components was increased,but too much water re-duced the solubility of the organic components.The present 10:1ratio might be the optimal point to balance the solubilities of both organic and inorganic components.In all co-solvent reactions,0.05equiv.of tetrabutylammonium bromide (TBAB)was added in order to prevent the generation of palladium black and make the cata-lytic system more stable [23].Based on the above findings,a continuous flow capillary mic-roreactor was employed under the optimal conditions obtained from the batch reaction.When taking 2-iodobenzyl phenyl ether (1)to run the intramolecular direct coupling in the microreactor at 90°C,as time went by the precipitate formed during the reac-tion was adsorbed on the wall of capillary and increasingly accu-mulated,and finally the microreactor was clogged.Due to the short reaction time caused by clogging issue (less than 2h),the reaction in the microreactor only gave a 8.7%conversion and the selectivity was quite lower (7:1).As sonication enables the rapid dispersion of solids and benefits reactions which are the effects arise from cavitation [18,24],this gave us a clue to exposing the capillary coil to ultrasound irradiation,and might solve clogging problem of the microreactor.Fortunately,as ultrasound irradiation was applied,the blockage in the microreactor was easily removed Fig.1.Microreactor system.Entry Substrate Base Solvent Conversion (%)20a :20b 11K 2CO 3DMA 51.516:121Cs 2CO 3DMA 54.418:131DMAP DMA Trace –41DABCO DMA Trace –51KOAc DMA66.115:16b 1K 2CO 3DMA/H 2O (10:1)77.715:17b 1Cs 2CO 3DMA/H 2O (10:1)72.118:18b 1NaOAc DMA/H 2O (10:1)58.88:19b 1KOAc DMA/H 2O (10:1)90.114:110b 2KOAc DMA/H 2O (10:1)70.332:111b3KOAcDMA/H 2O(10:1)Trace–Reaction conditions:2-halobenzyl phenyl ether (0.5mmol),Pd(OAc)2and base were dissolved in each solvent (5.0mL)and heated to 100°C under nitrogen atmosphere for 24h.aDetermined by 1H NMR.b5mol%TBAB was added.obtained when 2-iodobenzyl phenyl ether 1as starting material run for 6h at 90°C (Table 2,entry 3),while batch reaction afforded 90%conversion for 24h at 100°C.However,the reaction selectivity improved very little by comparison with that of batch reaction.It is reported that for the intramolecular direct arylation,despite the fact that aryl iodides provide greater reactivity in cross-coupling reactions,aryl bromides afford better outcomes than aryl iodides [17],thus,a bromide of the substrate (2)was employed for the reaction to improve both conversion and selectivity.As expected,compared with batch reaction,the selectivity and conversion im-proved dramatically from 32:1to 44:1and 70%to 97%,respectively (Table 1,entry 10vs.Table 2,entry 6).While,batch reaction under irradiation afforded 56%conversion and 32:1selectivity.The re-sults confirmed that a combination use of microreactor and ultra-sound greatly benefited the reaction.With this optimal reaction conditions,the scope of the current procedure was examined.Taking the reaction superiority and cheap price into account,aryl bromides were used as substrates.The efficiency and functional tolerance of this procedure have been fully demonstrated by synthesizing a number of functionalized coupling products which bearing substitutes such as nitro,alde-hyde,ketone,ester,phenyl,methyl,methoxy,as well as protecting group tosyl and Bco.The results were outlined in Table 3.Interest-ingly,the electronic nature of the substituents seemed to have lit-tle effect on the product yields.Meaningfully,chloro substituents ether tether could be replaced by amine and amide,and afford the same high yields (entry 14,15).Poly fused N-heterocycles could be prepared in moderate to good results (entry 11-13and 17).Five membered O-heterocycles was also obtained in 97%yield (entry 18).Moreover,a high regioselectivity was observed in cases where direct arylation occurred at two chemically different arene positions,in this case,arylation arose at the more sterically acces-sible position (entry 2and 4).With meta-nitro and -t -butyl substi-tutes,only one product was observed from 1H NMR (entry2and 4).It is noteworthy that the quinolone core was successfully embed-ded in coupling product 38(entry 17)and the current reaction pro-vided a novel way to prepare the quinolone derivatives that possess various bioactivities [26].Conventional intramolecular direct arylation usually needed a higher temperature (above 120o C),complex ligands,additives (e.g.expensive silver salts or pivalic acid),inert atmosphere and a long reaction time (more than 8h)[11–13,22,27],these condi-tions were greatly meliorated in the current reaction procedure.3.ConclusionIn conclusion,we have described a mild and efficient intramo-lecular direct arylation of aryl bromides in a continuous flow cap-illary microreactor with assistance of ultrasonic irradiation.The intramolecular direct arylation was achieved with high selectivity,ligand-free,low temperature,broad substrate scope and compati-ble to complex chemical structures such as quinolone core.Fur-thermore,ultrasound irradiation not only greatly improved the reaction conversion and selectivity,but also solved the clogging problem of microreactor for solid-forming reactions and made the reaction run smoothly.Further research on aryl chloride intra-molecilar coupling and other solid-forming reactions in the mic-roreactor under ultrasound irradiation is underway in our lab.4.Experimental4.1.Reagents and apparatusAll reagents and solvents were used as supplied without further purification.For the batch reaction,all the experiments were .X RT Conversion (%)1X =I 268.918:12X =I 471.620:13X =I 698.4(89.3)17:14X =Br 241.942:15X =Br 467.650:16X =Br 696.7(92.1)44:17X =Cl 6Trace –8b X =Br 644.820:19cX =Br656.134:1RT:reaction time (hour).Conversion was determined by 1H NMR and the isolated yield is shown in parentheses.aDetermined by 1HNMR.bBatch reaction without ultrasound.cUltrasound-assisted batch reaction.Fig.2.Effects of the ratio of DMA to water on the conversion and selectivity.19(2012)250–256L.Zhang et al./Ultrasonics Sonochemistry19(2012)250–256253Table3Biaryl formation in microreactor under ultrasound irradiation.(continued on next page)Scientific Equipment Co.,Ltd.;syringe was SGE supplied by Beijing Huadr Science and Technology Co.,Ltd.;capillary was purchased from Yongnian Ruipu Chromatogram Equipment Co.,Ltd.;1H NMR and 13C NMR were determined in CDCl 3on a Brucker 300or 500MHz spectrometer at room temperature,tetramethylsilane (TMS)served as an internal standard.EI-MS was taken on a QP2010GC–MS instrument (Shimadzu,Japan),ESI-MS and high resolution MS (HRMS)were carried out on a LTQ Orbitrap XL (The Thermo Scientific,USA).Sonication was performed in Kun-shan SB-3200DT ultrasonic cleaner with the frequency of 40kHz and an output power of 150W.4.2.General procedure for the synthesis of substrates 1–14,15,17,and 19(Table 3,entry1–8,12,14,15,16)The appropriate phenol or heterocycle compounds or sulfamide (1.2equiv.),K 2CO 3(or KOH for 12,13,14,and 15)(2equiv.)and DMF (or DMSO for 12,13,14,and 15)(0.5M)were placed in a round bottom flask equipped with a magnetic stir bar.Addition of the appropriate 2-halobenzylbromide (or 4-nitroflorobenzene for 19)(1equiv.)was followed by heating (60°C)of the reaction overnight.The reaction was allowed to cool and was diluted with water and extracted with Et 2O.The combined organic phase was washed by brine,dried over anhydrous Na 2SO 4,filtered and the volatiles were evaporated under reduced pressure.The residues were then purified via silica gel column chromatography usingethyl acetate/hexanes mixtures.Products were characterized by 1H NMR and MS (EI or ESI).4.3.Typical procedure for the synthesis of substrate 16(Table 3,entry 13)To a mixture of 2-halobenzoic acid (1equiv.),DCC (1.2equiv.),DMAP (0.1equiv.)and dichloromethane (0.25M)was added a solution of monomethylaniline (1.5equiv.)in dichloromethane (0.25M)in ice-water bath.When reaction complete,the mixture was filtered and washed with ether.Remove solvent under re-duced pressure.The residues were then purified via silica gel col-umn chromatography using ethyl acetate/hexanes mixtures to give substrate 16.Products were characterized by 1H NMR and EI-MS.4.4.General procedure for intramolecular direct arylation in the microreactor with assistance of ultrasonic irradiationA stock solution of the 2-halobenzyl phenyl ether (0.5mmol)and TBAB (0.05equiv.)in DMA (2.5mL)was prepared and taken up in a SGE gas-tight syringe.A second stock solution containing Pd(OAc)2(5mol%)and KOAc (2.0equiv.)in H 2O (0.45mL)and DMA (2.05mL)was also prepared and taken up in a second SGE gas-tight syringe.The syringes were placed on a TS2-60syringe pump which was set at different flow rates to meet differentTable 3(continued )Entry SubstrateRT Product Isolate yield 13395.914390.615696.016691.317376.618697.3RT:Reaction time (hour).254L.Zhang et al./Ultrasonics Sonochemistry 19(2012)250–256reaction times(Reaction time was calculated according to the fol-lowing equation:time(h)Âflow rate(l L/h)=volume of microre-actor(l L)).The two reactant streams were mixed in a1:1ratio through a micro static mixing Tee,and then delivered into a 500cm capillary coil with an inner diameter of530l m(Fig.1). The capillary coil was located in the maximum energy area in the ultrasonic generator and heated to90°C.The output from the reactor was quenched with Et2O/H2O immediately.The result-ing mixture was extracted with Et2O or EtOAc(3Â8mL)and the combined organic phase was washed with brine,dried over anhy-drous Na2SO4,and then the solvent was removed under reduced pressure.The residues were then purified via silica gel column chromatography using ethyl acetate/hexanes mixtures.Products were characterized by NMR,MS and HRMS(EI or ESI).4.5.Experimental data for compounds4.5.1.Substrates1–19The structures of the known compounds1–3,5–7,9,10,14–18 and21were identified by comparison the spectral data with those reported in the literatures[11–13,28–33].pound4.White solid;Yield:88.1%;1H NMR(300MHz, CDCl3)d7.62–7.59(m,2H),7.38(m,2H),7.24–7.13(m,2H),6.99–6.88(m,2H),5.20(s,2H),1.44(s,9H);EI-MS m/z(rel.int.,%):318 (12),169(100).pound8.White solid;Yield:96.8%;1H NMR(300MHz, CDCl3)d7.67–7.58(m,2H),7.55(dd,J=7.9,1.2Hz,1H),7.48–7.29 (m,6H),7.29–7.21(m,1H),7.16(dd,J=7.7,1.6Hz,1H),7.13–7.07 (m,1H),7.06–7.03(m,J=9.6,1.2Hz,1H),5.13(s,2H);EI-MS m/z (rel.int.,%):338(33),259,(28),169(100).pound11.White solid;Yield:95.6%;1H NMR (300MHz,CDCl3)d9.85(s,1H),7.59(dd,J=7.9,1.1Hz,1H),7.53 (d,J=7.7Hz,1H),7.45(d,J=1.8Hz,1H),7.41(dd,J=8.2,1.9Hz, 1H),7.33(td,J=7.6,1.1Hz,1H),7.19(td,J=7.8,1.6Hz,1H),6.96 (d,J=8.2Hz,1H), 5.30(s,2H), 3.97(s,3H);EI-MS m/z(rel. int.,%):320(11),169(100).pound12.White solid;Yield:96.0%;1H NMR (300MHz,CDCl3)d7.87(dd,J=7.8, 1.6Hz,1H),7.81(d, J=7.7Hz,1H),7.57(dd,J=8.0,1.0Hz,1H),7.53–7.43(m,1H), 7.38(td,J=7.6,1.0Hz,1H),7.19(td,J=8.0,1.6Hz,1H),7.02(dd, J=11.6, 4.3Hz,2H), 5.22(s,2H), 3.93(s,3H);EI-MS m/z(rel. int.,%):320(3),209(56),169(100).pound13.White solid;Yield:83.9%;1H NMR (300MHz,CDCl3)d8.03–7.85(m,2H),7.60(dd,J=7.9,1.1Hz, 1H),7.52(d,J=7.7Hz,1H),7.34(td,J=7.5,1.1Hz,1H),7.21(td, J=7.8,1.7Hz,1H),7.10–6.95(m,2H),5.20(s,2H),2.56(s,3H); EI-MS m/z(rel.int.,%):304(12),169(100).pound19.White solid;Yield:95.7%;1H NMR (300MHz,CDCl3)d7.60(d,J=7.9Hz,1H),7.53(d,J=7.6Hz,1H), 7.37–7.29(m,2H),7.25–7.15(m,2H),6.98–6.91(m,2H),5.15(s, 6H),4.38(s,6H),1.44(s,26H);MS(ESI):392(M+H).pound20.Pale yellow solid;Yield:81.5%;1H NMR (300MHz,CDCl3)d7.63(dd,J=7.4, 1.8Hz,1H),7.41(d, J=7.8Hz,1H),7.25–7.11(m,2H),6.81(dd,J=7.2,2.1Hz,1H), 6.31(d,J=2.1Hz,1H),6.24(d,J=7.7Hz,1H),6.01(d,J=2.1Hz, 1H),5.24(s,2H),3.94(s,3H),3.71(s,3H);MS(ESI):374(M+H).4.5.2.Coupling products22–39The structures of known coupling products23,25,27,28,32, 33,35,36and39were elucidated by comparison the spectral data with those reported in the literatures[11,13,27,30,31,33].pound22.White solid;1H NMR(300MHz,CDCl3)d 7.70(d,J=7.6Hz,1H),7.63(dd,J=7.7, 1.5Hz,1H),7.38(td, J=7.6, 1.5Hz,1H),7.31–7.26(m,2H),7.19(d,J=7.4Hz,1H), 7.02(t,J=7.7Hz,1H), 5.07(s,2H), 1.43(s,9H);13C NMR (75MHz,CDCl3)d153.61,139.03,131.80,130.83,128.35,127.33, 126.71,124.37,123.96,122.53,121.68,121.65,67.60,34.82, 29.80(3);EI-MS m/z(rel.int.,%):238(37),223(100),195(22), 165(22);HRMS(ESI):calculated for C17H18O+H=239.1436, found:239.1480.pound24.Pale yellow solid;1H NMR(300MHz,CDCl3) d7.95(dd,J=7.8,1.5Hz,1H),7.81(dd,J=8.2,1.5Hz,1H),7.70(d, J=7.4Hz,1H),7.46–7.35(m,2H),7.24–7.18(m,1H),7.13(t, J=8.0Hz,1H),5.26(s,2H);13C NMR(75MHz,CDCl3)d154.67, 146.11,136.73,135.13,135.08,134.29(s),133.09,133.84, 131.90,131.00,128.58,127.35,83.61,83.19,82.76,75.13;MS (ESI):228.05(M+H);HRMS(ESI):calculated for C13H9NO3+H=228.0661,found:228.0648.pound26.White solid;1H NMR(300MHz,CDCl3)d 7.95(d,J=2.2Hz,1H),7.79(d,J=7.6Hz,1H),7.68–7.57(m,2H), 7.49–7.29(m,6H),7.19(d,J=7.0Hz,1H),7.08(d,J=8.4Hz,1H), 5.17(s,2H);13C NMR(75MHz,CDCl3)d154.30,140.92,135.30, 131.40,129.98,128.74,128.45,128.22,127.77,126.90,126.84, 124.67,123.04,121.99,117.66,77.41,76.99,76.56,68.52;EI-MS m/z(rel.int.,%):258(100),257(85),228(17),229(14),215(6); HRMS(ESI):calculated for C19H14O+H=259.1123,found: 259.1101.pound29.White solid;1H NMR(300MHz,CDCl3)d 9.95(s,1H),7.89(d,J=1.7Hz,1H),7.76(d,J=7.6Hz,1H),7.50–7.30(m,3H),7.19(d,J=7.6Hz,1H),5.30(s,2H),3.98(s,3H); 13C NMR(75MHz,CDCl3)d190.79,149.62,149.08,130.79, 130.42,130.16,128.65,128.48,124.61,123.21,122.22,119.96, 109.58,68.87,56.04;MS(ESI):241.05(M+H);HRMS(ESI):calcu-lated for C15H12O3+H=241.0865,found:241.0847.pound30.White solid;1H NMR(300MHz,CDCl3)d 7.89(dd,J=7.7,1.6Hz,1H),7.75(dd,J=7.8,1.6Hz,1H),7.68(d, J=7.4Hz,1H),7.39(td,J=7.5, 1.1Hz,1H),7.32(td,J=7.4, 1.2Hz,1H),7.18(d,J=7.3Hz,1H),7.08(t,J=7.8Hz,1H),5.20(s, 2H), 3.92(s,3H);13C NMR(75MHz,CDCl3)d166.27,154.48, 134.84,133.30,131.13,129.22,128.50,128.06,127.16,124.60, 124.52,124.12,122.13,121.20,68.56,52.03;MS(ESI):241.05 (M+H);HRMS(ESI):calculated for C15H12O3+H=241.0865, found:241.0848.pound31.White solid;1H NMR(300MHz,CDCl3)d 8.40(d,J=2.1Hz,1H),7.85(dd,J=8.5, 2.1Hz,1H),7.81(d, J=7.7Hz,1H),7.42(t,J=7.1Hz,1H),7.33(td,J=7.4,1.1Hz,1H), 7.17(d,J=7.4Hz,1H),7.02(d,J=8.5Hz,1H),5.20(s,2H),2.62 (s,3H);13C NMR(75MHz,CDCl3)d196.68,158.64,131.38, 130.59,130.07,128.90,128.61,128.22,124.58,123.74,122.44, 122.10,117.25,68.48,26.31;MS(ESI):225.05(M+H);HRMS (ESI):calculated for C15H12O2+H=225.0916,found:225.0894.pound34.Pale solid;1H NMR(300MHz,CDCl3)d7.77 (d,J=7.6Hz,1H),7.61(d,J=7.8Hz,1H),7.46(d,J=7.5Hz,1H), 7.41(t,J=7.6Hz,1H),7.30(dd,J=11.3, 4.4Hz,2H),7.20(t, J=6.9Hz,1H),7.11(t,J=7.5Hz,1H),5.05(s,2H),2.57(s,3H);13C NMR(75MHz,CDCl3)d141.63,140.01,133.59,133.55,L.Zhang et al./Ultrasonics Sonochemistry19(2012)250–256255133.04,127.92,126.23,123.45,121.36,120.75,119.49,118.72, 108.98,101.90,47.94,8.94;MS(ESI):220.05(M+H);HRMS (ESI):calculated for C16H13N+H=220.1126,found:220.1104.pound37.White solid;1H NMR(300MHz,CDCl3)d 7.73–7.63(m,2H),7.38(t,J=7.6Hz,1H),7.30(dd,J=7.4,1.2Hz, 1H),7.24(d,J=9.6Hz,2H),7.16(d,J=6.8Hz,1H),7.02(t, J=7.6Hz,1H),5.14(s,2H),4.34(s,2H),1.44(s,9H);13C NMR (75MHz,CDCl3)d155.82,152.59,131.01,129.90,129.26,128.45, 127.64,127.32,124.53,122.74,122.55,122.14,121.75,79.17, 68.37,40.08,28.36;MS(ESI):312.15(M+H);HRMS(ESI):calcu-lated for C19H21NO3+H=312.1600,found:312.1571.pound38.Pale solid;1H NMR(300MHz,CDCl3)d7.68 (d,J=7.3Hz,1H),7.62–7.42(m,3H),6.56(s,1H),6.23(s,2H),5.12 (s,2H),3.91(s,6H);13C NMR(75MHz,CDCl3)d178.09,162.94, 161.79,149.55,142.33,137.66,133.34,130.71,128.42,122.79, 121.67,110.54,103.14,94.55,89.26,56.01,55.60,54.41;MS (ESI):294.05(M+H);HRMS(ESI):calculated for C18H15NO3+H=294.1130,found:294.1096.AcknowledgementThis work was supported by973Program(2007CB714504)and National Natural Science Foundation of China(20821063, 90913023).The authors thank Dr.Yin Ding(Nanjing University, China)for HRMS measurements.References[1]M.C.Kozlowski,B.J.Morgan,E.C.Linton,Total synthesis of chiral biaryl naturalproducts by asymmetric biaryl coupling,Chem.Soc.Rev.38(2009)3193–3207.[2]H.Guinaudeau,M.Leboeuf,A.Cave,Aporphine alkaloids.2,J.Nat.Prod.42(1979)325–360.[3]J.M.Brunel,BINOL:a versatile chiral reagent,Chem.Rev.105(2005)857–897.[4]R.Noyori,H.Takaya,BINAP–an efficient chiral element for asymmetriccatalysis,Acc.Chem.Res.23(1990)345–350.[5]J.Hassan,M.Sevignon, C.Gozzi, E.Schulz,M.Lemaire,Aryl–aryl bondformation one century after the discovery of the Ullmann reaction,Chem.Rev.102(2002)1359–1469.[6]T.Satoh,M.Miura,Catalytic direct arylation of heteroaromatic compounds,Chem.Lett.36(2007)200–205.[7]D.Alberico,M.E.Scott,utens,Aryl–aryl bond formation by transition-metal-catalyzed direct arylation,Chem.Rev.107(2007)174–238.[8]G.B.Bajracharya,O.Daugulis,Direct transition-metal-free intramoleculararylation of phenols,Org.Lett.10(2008)4625–4628.[9]D.D.Hennings,S.Iwasa,V.H.Rawal,Anion-accelerated palladium-catalyzedintramolecular coupling of phenols with aryl halides,.Chem.62(1997) 2–3.[10]F.Bellina,R.Rossi,Recent advances in the synthesis of(hetero)aryl-substitutedheteroarenes via transition metal-catalysed direct(hetero)arylation of heteroarene C–H bonds with aryl halides or pseudohalides,diaryliodonium salts,and potassium aryltrifluoroborates,Tetrahedron65(2009)10269–10310.[11]L.C.Campeau,M.Parisien,M.Leblanc,K.Fagnou,Biaryl synthesis via directarylation:establishment of an efficient catalyst for intramolecular processes,J.Am.Chem.Soc.126(2004)9186–9187.[12]M.Parisien, D.Valette,K.Fagnou,Direct arylation reactions catalyzed byPd(OH)(2)/C:evidence for a soluble palladium catalyst,.Chem.70(2005) 7578–7584.[13]L.C.Campeau,M.Parisien,A.Jean,K.Fagnou,Catalytic direct arylation witharyl chlorides,bromides,and iodides:intramolecular studies leading to new intermolecular reactions,J.Am.Chem.Soc.128(2006)581–590.[14]B.P.Mason,K.E.Price,J.L.Steinbacher,A.R.Bogdan,D.T.McQuade,Greenerapproaches to organic synthesis using microreactor technology,Chem.Rev.107(2007)2300–2318.[15]J.C.Brandt,S.C.Elmore,R.I.Robinson,T.Wirth,Safe and efficient ritterreactions inflow,Synlett(2010)3099–3103.[16]P.Watts,S.J.Haswell,The application of micro reactors for organic synthesis,Chem.Soc.Rev.34(2005)235–246.[17]S.L.Poe,M.A.Cummings,M.R.Haaf, D.T.McQuade,Solving the cloggingproblem:precipitate-forming reactions inflow,Angew.Chem.Int.Ed.45 (2006)1544–1548.[18]P.Cintas,J.L.Luche,Green chemistry–The sonochemical approach,GreenChem.1(1999)115–125.[19]R.Rajagopal,D.V.Jarikote,K.V.Srinivasan,Ultrasound promoted Suzuki cross-coupling reactions in ionic liquid at ambient conditions,mun.(2002)616–617.[20]J.T.Li,J.F.Han,J.H.Yang,T.S.Li,An efficient synthesis of3,4-dihydropyrimidin-2-ones catalyzed by NH2SO3H under ultrasound irradiation,Ultrason.Sonochem.10(2003)119–122.[21]J.Jin,M.M.Cai,J.X.Li,Highly efficient suzuki coupling of aryl chlorides in acontinuousflow capillary microreactor,Synlett(2009)2534–2538.[22]D.E.Ames, A.Opalko,Palladium-catalyzed cyclization of2-substitutedhalogenoarenes by dehydrohalogenation,Tetrahedron40(1984)1919–1925.[23]J.H.Li,W.J.Liu,Y.X.Xie,Recyclable and reusable Pd(OAc)(2)/DABCO/PEG-400system for Suzuki–Miyaura cross-coupling reaction,.Chem.70(2005) 5409–5412.[24]S.Koda,T.Kimura,T.Kondo,H.Mitome,A standard method to calibratesonochemical efficiency of an individual reaction system,Ultrason.Sonochem.10(2003)149–156.[25]T.Noël,J.R.Naber,R.L.Hartman,J.P.McMullen,K.F.Jensen,S.L.Buchwald,Palladium-catalyzed amination reactions inflow:overcoming the challenges of clogging via acoustic irradiation,Chem.Sci.2(2011)287–290.[26]G.B.Liu,J.L.Xu,C.C.He,G.Chen,Q.Xu,H.X.Xu,J.X.Li,Synthesis and evaluationof a novel series of quinoline derivatives with immunosuppressive activity, Bioorgan.Med.Chem.17(2009)5433–5441.[27]france,pointe,K.Fagnou,Mild and efficient palladium-catalyzedintramolecular direct arylation reactions,Tetrahedron64(2008)6015–6020.[28]J.Forrester,R.V.H.Jones,L.Newton,P.N.Preston,Synthesis and reactivity ofbenzylic sulfonium salts:benzylation of phenol and thiophenol under near-neutral conditions,Tetrahedron57(2001)2871–2884.[29]B.J.Margolis,J.J.Swidorski, B.N.Rogers,An efficient assembly ofheterobenzazepine ring systems utilizing an intramolecular palladium-catalyzed cycloamination,.Chem.68(2003)644–647.[30]Y.Antonio,M.E.Delacruz,E.Galeazzi,A.Guzman,B.L.Bray,R.Greenhouse,L.J.Kurz,D.A.Lustig,M.L.Maddox,J.M.Muchowski,Oxidative radical cyclization to pyrroles under reducing conditions–reductive desulfonylation of alpha-sulfonylpyrroles with tri-n-butyltin hydride,Can.J.Chem.72(1994)15–22.[31]N.Barbero,R.SanMartin,E.Dominguez,Divergent synthesis of isoindolo2,1-aindole and indolo1,2-a indole through copper-catalysed C-and N-arylations, Tetrahedron Lett.50(2009)2129–2131.[32]S.R.Flanagan,D.C.Harrowven,M.Bradley,Radical cyclisation reactions withindoles,Tetrahedron Lett.44(2003)1795–1798.[33]D.E.Ames, A.Opalko,Synthesis of dibenzofurans by palladium-catalyzedintramolecular dehydrobromination of2-bromophenyl phenyl ethers, Synthesis-Stuttgart(1983)234–235.256L.Zhang et al./Ultrasonics Sonochemistry19(2012)250–256。
超声增强的输送的物料进入并通过皮肤 翻译
Ultrasound-enhanced delivery of materials into and through the skinA method for enhancing the permeability of the skin or other biological membrane to a material such as a drug is disclosed. In the method, the drug is delivered in conjunction with ultrasound having a frequency of above about 10 MHz. The method may also be used in conjunction with chemical permeation enhancers and/or with iontophoresis.图片(11)权利要求(21)We claim:1. A method for enhancing the rate of permeation of a drug medium into a selected intact area of an individual's body surface, which method comprises:(a) applying ultrasound having a frequency of above 10 MHz to said selected area, at an intensity and for a period of time effective to enhance the permeability of said selected area;(b) contacting the selected area with the drug medium; and(c) effecting passage of said drug medium into and through said selected area by means of iontophoresis.2. The method of claim 1, wherein said ultrasound frequency is in the range of about 15 MHz to 50 MHz.3. The method of claim 2, wherein said ultrasound frequency is in the range of about 15 to 25 MHz.4. The method of claim 1, wherein said period of time is in the range of about 5 to 45 minutes.5. The method of claim 4, wherein said period of time is in the range of about 5 to 30 minutes.6. The method of claim 1, wherein said period of time is less than about 10 minutes.7. The method of claim 1, wherein said intensity of said ultrasound is less than about 5.0W/cm.sup.2.8. The method of claim 7, wherein said intensity of said ultrasound is in the range of about 0.01 to 5.0 W/cm.sup.2.9. The method of claim 8, wherein said intensity of said ultrasound is in the range of about 0.05 to 3.0 W/cm.sup.2.10. The method of claim 1, wherein said area of the stratum corneum is in the range of about 1 to 100 cm.sup.2.11. The method of claim 10, wherein said area of the stratum corneum is in the range of about 5 to 100 cm.sup.2.12. The method of claim 11, wherein said area of the stratum corneum is in the range of about 10 to 50 cm.sup.2.13. The method of claim 1 wherein said drug medium comprises a drug and a coupling agent effective to transfer said ultrasound to the body from an ultrasound source.14. The method of claim 13 wherein said coupling agent is a polymer or a gel.15. The method of claim 13 wherein said coupling agent is selected from the group consisting of glycerin, water, and propylene glycol.16. The method of claim 1 wherein said drug medium further comprises a chemical permeation enhancer.17. The method of claim 1, wherein steps (a) and (b) are carried out approximately simultaneously.18. The method of claim 1, wherein step (b) is carried out before step (a).19. The method of claim 1, wherein step (a) is carried out before step (b).20. The method of claim 1, wherein the ultrasound is applied continuously.21. The method of claim 1, wherein the ultrasound is pulsed.说明This application is a division of application Ser. No. 07/844,732 filed Mar. 2, 1992, now U.S. Pat. No. 5,231,975 which is a divisional of application Ser. No. 07/484,560, now U.S. Pat. No. 5,115,805, filed Feb. 23, 1990.TECHNICAL FIELDThis invention relates generally to the field of drug delivery. More particularly, the invention relates to a method of enhancing the rate of permeation of topically, transmucosally or transdermally applied materials using high frequency ultrasound.BACKGROUNDThe delivery of drugs through the skin ("transdermal drug delivery" or "TDD") provides many advantages; primarily, such a means of delivery is a comfortable, convenient and non-invasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.Skin is a structurally complex, relatively impermeable membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the stratum corneum, a layer approximately 5-15 micrometers thick over most of the body, which presents the primary barrier to absorption of topical compositions or transdermally administered drugs. It is believed to be the high degree of keratinization within its cells as well as their dense packing and cementation by ordered, semicrystalline lipids which create in many cases a substantially impermeable barrier to drug penetration. Applicability of transdermal drug delivery is thus presently limited, because the skin is such an excellent barrier to the ingress of topically applied materials. For example, many of the new peptides and proteins now produced as a result of the biotechnology revolution cannot be delivered across the skin in sufficient quantities due to their naturally low rates of skin permeability.Various methods have been used to increase skin permeability, and in particular to increase the permeability of the stratum corneum (i.e., so as to achieve enhanced penetration, through the skin, of the drug to be administered transdermally). The primary focus has been on the use of chemical enhancers, i.e., wherein drug is coadministered with a penetration enhancing agent (or "permeation enhancer"). While such compounds are effective in increasing the rate at which drug is delivered through the skin, there are drawbacks with many permeation enhancers which limit their use. For example, many permeation enhancers are associated with deleterious effects on the skin (e.g., irritation). In addition, control of drug delivery with chemical enhancement can be quite difficult.Iontophoresis has also been used to increase the permeability of skin to drugs, and involves (1) the application of an external electric field, and (2) topical delivery of an ionized form of drug (or of a neutral drug carried with the water flux associated with ion transport, i.e., via "electroosmosis"). While permeation enhancement via iontophoresis has, as with chemical enhancers, been effective, there are problems with control of drug delivery and the degree of irreversible skin damage induced by the transmembrane passage of current.The presently disclosed and claimed method involves the use of ultrasound to decrease the barrier function of the stratum corneum and thus increase the rate at which a drug may be delivered through the skin. "Ultrasound" is defined as mechanical pressure waves with frequencies above 20,000 Hz (see, e.g., H. Lutz et al., Manual of Ultrasound: 1. Basic Physical and Technical Principles (Berlin: Springer-Verlag, 1984)).As discussed by P. Tyle et al. in Pharmaceutical Research 6(5):355-361 (1989), drug penetration achieved via "sonophoresis" (the movement of drugs through skin under the influence of an ultrasonic perturbation; see D. M. Skauen and G. M. Zentner, Int. J. Pharmaceutics 20:235-245 (1984)), is believed to result from thermal, mechanical and chemical alteration of biological tissues by the applied ultrasonic waves. Unlike iontophoresis, the risk of skin damage appears to be low.Applications of ultrasound to drug delivery have been discussed in the literature. See, for example: P. Tyle et al., supra (which provides an overview of sonophoresis); S. Miyazaki et al., J. Pharm. Pharmacol. 40:716-717 (1988) (controlled release of insulin from a polymer implant using ultrasound); J. Kost et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater.16(141):294-295 (1989) (overview of the effect of ultrasound on the permeability of human skin and synthetic membranes); H. Benson et al., Physical Therapy 69(2):113-118 (1989) (effect of ultrasound on the percutaneous absorption of benzydamine); E. Novak, Arch. Phys. Medicine & Rehab. 45:231-232 (1964) (enhanced penetration of lidocaine through intact skin using ultrasound); J. E. Griffin et al., Amer. J. Phys. Medicine 44(1):20-25 (1965) (ultrasonic penetration of cortisol into pig tissue); J. E. Griffin et al., J. Amer. Phys. Therapy Assoc.46:18-26 (1966) (overview of the use of ultrasonic energy in drug therapy); J. E. Griffin et al., Phys. Therapy 47(7):594-601 (1967) (ultrasonic penetration of hydrocortisone); J. E. Griffin et al., Phys. Therapy 48(12):1336-1344 (1968) (ultrasonic penetration of cortisol into pig tissue); J. E. Griffin et al., Amer. J. Phys. Medicine 51(2):62-72 (1972) (same); J. C. McElnay, Int. J. Pharmaceutics 40:105-110 (1987) (the effect of ultrasound on the percutaneous absorption of fluocinolone acetonide); and C. Escoffier et al., Bioeng. Skin 2:87-94 (1986) (in vitro study of the velocity of ultrasound in skin).In addition to the aforementioned art, U.S. Pat. Nos. 4,767,402 and 4,780,212 to Kost et al. relate specifically to the use of specific frequencies of ultrasound to enhance the rate of permeation of a drug through human skin or through a synthetic membrane.While the application of ultrasound in conjunction with drug delivery is thus known, results have for the most part been disappointing, i.e., enhancement of skin permeability has been relatively low.SUMMARY OF THE INVENTIONThe present invention provides a novel method for enhancing the rate of permeation of a given material through a selected intact area of an individual's body surface. The method comprises contacting the selected intact area with the material and applying ultrasound to the contacted area. The ultrasound preferably has a frequency of above about 10 MHz, and is continued at an intensity and for a period of time sufficient to enhance the rate of permeation of the material into and through the body surface. The ultrasound can also be used to pretreat the selected area of the body surface in preparation for drug delivery, or for diagnostic purposes, i.e., to enable non-invasive sampling of physiologic material beneath the skin or body surface.In addition to enhancing the rate of permeation of a material, the present invention involves increasing the permeability of a biological membrane such as the stratum corneum by applying ultrasound having a frequency of above about 10 MHz to the membrane at an intensity and for a period of time sufficient to give rise to increased permeability of the membrane. Once the permeability of the membrane has been increased, it is possible to apply a material thereto and obtain an increased rate of flow of the material through the membrane.It is accordingly a primary object of the invention to address the aforementioned deficiencies of the prior art by providing a method of enhancing the permeability of biological membranes and thus allow for an increased rate of delivery of material therethrough.It is another object of the invention to provide such a method which is effective with or without chemical permeation enhancers.It is still another object of the invention to minimize lag time in such a method and provide a relatively short total treatment time.It is yet another object of the invention to provide such a method in which drug delivery is effected using ultrasound.It is a further object of the invention to enable sampling of tissue beneath the skin or other body surface by application of high frequency (>10 MHz) ultrasound thereto.A further feature of the invention is that it preferably involves ultrasound of a frequency greater than about 10 MHz.Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.BRIEF DESCRIPTION OF THE DRAWINGSFIGS. 1A, 1B and 1C are theoretical plots of energy dissipation within the skin barrier versus frequency of applied ultrasound.FIGS. 2, 3 and 4 are graphic representations of the amount of salicylic acid recovered from the stratum corneum after ultrasound treatment at different frequencies.FIGS. 5 and 6 represent the results of experiments similar to those summarized in FIGS. 2, 3 and 4, but with a shorter treatment time.FIGS. 7, 8, 9 and 10 are plots of enhancement versus "tape-strip number," as described in the Example.FIG. 11 illustrates the effect of ultrasound on the systemic availability of salicylic acid following topical application.DETAILED DESCRIPTION OF PREFERRED EMBODIMENTSBefore the present method of enhancing the rate of permeation of a material through a biological membrane and enhancing the permeability of membranes using ultrasound are disclosed and described, it is to be understood that this invention is not limited to the particular process steps and materials disclosed herein as such process steps and materials may, of course, vary. It is alto to be understood that the terminology used herein is used for purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited only by the appended claims.It must be noted that as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to "a drug" includes mixtures of drugs and their pharmaceutically acceptable salts, reference to "an ultrasound device" includes one or more ultrasound devices of the type necessary for carrying out the present invention, and reference to "the method of administration" includes one or more different methods of administration known to those skilled in the art or which will become known to those skilled in the art upon reading this disclosure.In one aspect of the invention a method is provided for enhancing the permeation of a given material such as a drug, pharmacologically active agent, or diagnostic agent into and/or through a biological membrane on an individual's body surface, which method comprises: (a) contacting the membrane with the chosen material in a pharmacologically acceptable carrier medium; and (b) applying ultrasound of an intensity and for a treatment time effective to produce delivery of the material through the membrane. The material is preferably a drug and it is preferable to obtain a desired blood level of the drug in the individual. The ultrasound is of a frequency and intensity effective to increase the permeability of the selected area to theapplied drug over that which would be obtained without ultrasound. The ultrasound preferably has a frequency of more than 10 MHz, and may be applied either continuously or pulsed, preferably continuously. The ultrasound may be applied to the skin either before or after application of the drug medium so long as administration of the ultrasound and the drug medium is relatively simultaneous, i.e., the ultrasound is applied within about 6, more preferably within about 4, most preferably within about 2 minutes of drug application.The invention is useful for achieving transdermal permeation of pharmacologically active agents which otherwise would be quite difficult to deliver through the skin or other body surface. For example, proteinaceous drugs and other high molecular weight pharmacologically active agents are ideal candidates for transdermal, transmucosal or topical delivery using the presently disclosed method. In an alternative embodiment, agents useful for diagnostic purposes may also be delivered into and/or through the body surface using the present method.The invention is also useful as a non-invasive diagnostic technique, i.e., in enabling the sampling of physiologic material from beneath the skin or other body surface and into a collection (and/or evaluation) chamber.The present invention will employ, unless otherwise indicated, conventional pharmaceutical methodology and more specifically conventional methodology used in connection with transdermal delivery of pharmaceutically active compounds and enhancers.In describing the present invention, the following terminology will be used in accordance with the definitions set out below.A "biological membrane" is intended to mean a membrane material present within a living organism which separates one area of the organism from another and, more specifically, which separates the organism from its outer environment. Skin and mucous membranes are thus included."Penetration enhancement" or "permeation enhancement" as used herein relates to an increase in the permeability of skin to a material such as a pharmacologically active agent, i.e., so as to increase the rate at which the material permeates into and through the skin. The present invention involves enhancement of permeation through the use of ultrasound, and, in particular, through the use of ultrasound having a frequency of greater than 10 MHz."Transdermal" (or "percutaneous") shall mean passage of a material into and through the skin to achieve effective therapeutic blood levels or deep tissue therapeutic levels. While the invention is described herein primarily in terms of "transdermal" administration, it will be appreciated by those skilled in the art that the presently disclosed and claimed method also encompasses the "transmucosal" and "topical" administration of drugs using ultrasound. "Transmucosal" is intended to mean passage of any given material through a mucosal membrane of a living organism and more specifically shall refer to the passage of a materialfrom the outside environment of the organism, through a mucous membrane and into the organism. "Transmucosal" administration thus includes delivery of drugs through either nasal or buccal tissue. By "topical" administration is meant local administration of a topical pharmacologically active agent to the skin as in, for example, the treatment of various skin disorders or the administration of a local anaesthetic. "Topical" delivery can involve penetration of a drug into the skin but not through it, i.e., topical administration does not involve actual passage of a drug into the bloodstream."Carriers" or "vehicles" as used herein refer to carrier materials without pharmacological activity which are suitable for administration with other pharmaceutically active materials, and include any such materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is nontoxic and which does not interact with the drug to be administered in a deleterious manner. Examples of suitable carriers for use herein include water, mineral oil, silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes, petroleum jelly, and a variety of other oils and polymeric materials.By the term "pharmacologically active agent" or "drug" as used herein is meant any chemical material or compound suitable for transdermal or transmucosal administration which can either (1) have a prophylactic effect on the organism and prevent an undesired biological effect such as preventing an infection, (2) alleviates a condition caused by a disease such as alleviating pain caused as a result of a disease, or (3) either alleviates or completely eliminates the disease from the organism. The effect of the agent may be local, such as providing for a local anaesthetic effect or it may be systemic. Such substances include the broad classes of compounds normally delivered through body surfaces and membranes, including skin. In general, this includes: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers. By the method of the present invention, both ionized and nonionzed drugs may be delivered, as can drugs of either high or low molecular weight.Proteinaceous and polypeptide drugs represent a preferred class of drugs for use in conjunction with the presently disclosed and claimed invention. Such drugs cannot generally be administered orally in that they Are often destroyed in the G.I. tract or metabolized in the liver. Further, due to the high molecular weight of most polypeptide drugs, conventional transdermal delivery systems are not generally effective. It is also desirable to use the methodof the invention in conjunction with drugs to which the permeability of the skin is relatively low, or which give rise to a long lag-time (application of ultrasound as described herein has been found to significantly reduce the lag-time involved with the transdermal administration of most drugs).By a "therapeutically effective" amount of a pharmacologically active agent is meant a nontoxic but sufficient amount of a compound to provide the desired therapeutic effect. The desired therapeutic effect may be a prophylactic effect, in preventing a disease, an effect which alleviates a system of the disease, or a curative effect which either eliminates or aids in the elimination of the disease.As noted above, the present invention is a method for enhancing the rate of permeation of a drug through an intact area of an individual's body surface, preferably the human skin. The method involves transdermal administration of a selected drug in conjunction with ultrasound. Ultrasound causes thermal, mechanical and chemical alterations of biological tissue, thereby enhancing the rate of permeation of a given material therethrough.While not wishing to be bound by theory, applicants propose that the use of higher frequency ultrasound as disclosed herein specifically enhances the permeation of the drug through the outer layer of skin, i.e., the stratum corneum, by causing momentary and reversible perturbations within (and thus short-term, reversible reduction in the barrier function of) the layer of the stratum corneum. It will be appreciated by those skilled in the art of transdermal drug delivery that a number of factors related to the present method will vary with the drug to be administered, the disease or injury to be treated, the age of the selected individual, the location of the skin to which the drug is applied, and the like.As noted above, "ultrasound" is ultrasonic radiation of a frequency above 20,000 Hz. As may be deduced from the literature cited above, ultrasound used for most medical purposes typically employs frequencies ranging from 1.6 to about 10 MHz. The present invention, by contrast, employs ultrasound frequencies of greater than about 10 MHz, preferably in the range of about 15 to 50 MHz, most preferably in the range of about 15 to 25 MHz. It should be emphasized that these ranges are intended to be merely illustrative of the preferred embodiment; in some cases higher or lower frequencies may be used.The ultrasound may be pulsed or continuous, but is preferably continuous when lower frequencies are used. At very high frequencies, pulsed application will generally be preferred so as to enable dissipation of generated heat.The preferred intensity of the applied ultrasound is less than about 5.0 W/cm.sup.2, more preferably is in the range of about 0.01 to 5.0 W/cm.sup.2, and most preferably is in the range of 0.05 to 3.0 W/cm.sup.2. The total treatment time, i.e., the period over which drug and ultrasound are administered, will vary depending on the drug administered, the disease or injury treated, etc., but will generally be on the order of about 30 seconds to 60 minutes, preferably 5 to 45 minutes, more preferably 5 to 30 minutes, and most preferably 5 to 10minutes. It should be noted that the aforementioned ranges represent suggested, or preferred, treatment times, but are not in any way intended to be limiting. Longer or shorter times may be possible and in some cases desirable. Virtually any type of device may be used to administer the ultrasound, providing that the device is callable of producing the higher frequency ultrasonic waves required by the present method. A device will typically have a power source such as a small battery, a transducer, a reservoir in which the drug medium is housed (and which may or may not be refillable), and a means to attach the system to the desired skin site.As ultrasound does not transmit well in air, a liquid medium is generally needed to efficiently and rapidly transmit ultrasound between the ultrasound applicator and the skin. As explained by P. Tyle et al., cited above, the selected drug medium should contain a "coupling" or "contacting" agent typically used in conjunction with ultrasound. The coupling agent should have an absorption coefficient similar to that of water, and furthermore be nonstaining, nonirritating to the skin, and slow drying. It is clearly preferred that the coupling agent retain a paste or gel consistency during the time period of ultrasound administration so that contact is maintained between the ultrasound source and the skin. Examples of preferred coupling agents are mixtures of mineral oil and glycerine and propylene glycol, oil/water emulsions, and a water-based gel. A solid-state, non-crystalline polymeric film having the above-mentioned characteristics may also be used. The drug medium may also contain a carrier or vehicle, as defined alone.A transdermal patch as well known in the art may be used in conjunction with the present invention, i.e., to deliver the drug medium to the skin. The "patch", however, must have the properties of the coupling agent as described in the preceding paragraph so as to enable transmission of the ultrasound from the applicator, through the patch, to the skin.As noted earlier in this section, virtually any chemical material or compound suitable for transdermal, transmucosal or topical administration may be administered using the present method. Again, the present invention is particularly useful to enhance delivery of proteinaceous and other high molecular weight drugs.The method of the invention is preferably carried out as follows. The drug medium, i.e., containing the selected drug or drugs in conjunction with the coupling agent and optionally a carrier or vehicle material, is applied to an area of intact body surface. Ultrasound preferably having a frequency greater than about 10 MHz may be applied before or after application of the drug medium, but is preferably applied immediately before application of the drug so as to "pretreat" the skin prior to drug administration.It should also be pointed out that the present method may be used in conjunction with a chemical permeation enhancer as known in the art, wherein the ultrasound enables the use of much lower concentrations of permeation enhancer--thus minimizing skin irritation and other problems frequently associated with such compounds--than would be possible in the absence of ultrasound. The permeation enhancer may be incorporated into the drug medium or it may。