WO2006030534A1

WO2006030534A1 - Integrated system for noninvasive focused energy treatment using energy activated drugs

Info

Publication number: WO2006030534A1
Application number: PCT/JP2004/014119
Authority: WO
Inventors: Ehud Baron
Original assignee: I-Check, Inc.
Priority date: 2004-09-17
Filing date: 2004-09-17
Publication date: 2006-03-23

Abstract

A system for noninvasive delivering and activating therapeutic agents within the body is disclosed. Especially the system pertains to drug delivery system, i. e., the system delivering an energy actevated drug encapsulated in microbubbles the rupture of which due to exposure to extracorporeal irradiation of ultrasound energy results in yielding a therapeutic effect.

Description

DESCRIPTION

Integrated system for noninvasive focused energy treatment

using energy activated drugs

BACKGROUND OF THE INVENTION

The present invention relates generally to systems and methods for performing therapeutic procedures using extracorporeal focused energy and treating biological tissues with energy activated drugs. More particularly, to systems and methods for treating biological tissues by delivering energy activated drug to a biological tissue and exposing the energy activated drug to extracorporeal focused ultrasound energy in a target tissue regions.

Noninvasive drug delivery system that is targeted and timed is very advantageous for the patients. The therapeutically effect is achieved by using acoustic cavitations for preparing the micro¬ encapsulated drug and focused energy for activating the drug in the targeted tissues on the right time. Noninvasive treatment procedures are considered to replace a big part of the invasive and traumatic medical interventions and to become the trend of the future. The employed ultrasonic acoustic waves and electromagnetic energy are non ionizing energy, and therefore do not compromise patient's health as heavy ion particle radiotherapy or X-Ray radiation therapy might be. The last kinds of radiation therapy are also very expensive both in equipment and highly qualified surgeons. Therefore, a noninvasive method and systems which can be safe to the patients and affordable to every hospital and clinic, preferably operated by paramedics under the suitable direction of a doctor, can make the treatment effective and wide spread. Prior art includes therapeutic usage of high intensity focused ultrasound and destroying the target tissue through generating a thermal effect. High intensity focused Ultrasonic energy is absorbed by a living tissue, increasing the temperature of a disease region and causing coagulation and necrosis. I.e., the absorbed energy heats the tissue cells in the target region to temperatures that exceed protein denaturizing thresholds (usually above 60 Celsius degrees), resulting in coagulation and necrosis. During a focused ultrasound procedure, small gas bubbles, or "microbubbles," may be generated in the liquid contained in the tissue when the ultrasonic waves are transmitted. The microbubbles may be formed due to tissue heating, the stress resulting from negative pressure produced by the propagating ultrasonic wave. Generally, steps are taken to avoid creating microbubbles in the tissue, because once created, they may collapse due to the applied stress from an acoustic field. Vortman et al, in US patent application 20030187371, teach us how to use the microbubbles to achieve a better heating effect, without letting the microbubbles rupture. This mechanism, called "cavitation," may cause extensive tissue damage and may be difficult to control. U.S. Pat. No. 6,309,355 discloses using cavitation induced by an ultrasound beam to create a surgical lesion.

Using high intensity convergent ultrasonic wave has a problem related to focusing. The problem is that when the convergent ultrasonic wave is focused off the disease region, a non-disease region of a human body is damaged. Since the resolution of ablative apparatus today is limited, there is always the danger of damaging neighboring tissues, like nerves, blood vessels, etc. This problem limits the value of ultrasound ablation as it is limited to the core of the tumor but not to its edges. Besides it requires prolonged usage of expensive imaging devices like MRI and of course continuous attention of a trained surgeon.

!UBSTITUTE SHEET(RULE26) Another usage of therapeutic ultrasound is by chemical interaction. The interaction is between a chemical substance existing in a disease region and a radiated ultrasonic wave. E.g. a remedy using a substance that generates active oxygen when an ultrasonic wave is radiated is proposed by Umemura and others and is named a sonodynamic therapy. Acoustic cavitation is considered to play an important role in a mechanism in which therapeutical effect is obtained by the sonodynamic therapy.

Cavitation results when gas dissolved in a solution forms bubbles under certain types of acoustic vibration. Cavitation can also occur when small bubbles already present in the solution oscillate or repeatedly enlarge and shrink.. When the size of these cavitation bubbles reaches a size that cannot be maintained, they suddenly collapse and release various types of energy. The various types of energy include, but are not limited to, mechanical energy, visible light, ultraviolet light, and other types of electromagnetic radiation. Heat, plasma, magnetic fields, shock waves, free radicals, heat and other forms of energy are also thought to be generated locally. The light activated drug is believed to be activated by at least one of the various forms of energy generated at the time of cavitation collapse. In Japanese published examined patent application Hei6-29196, a method of using a substance that generates active oxygens by the chemical effect of ultrasound exposure is disclosed. A substance such as porphyrin used in the technique has a function of secondarily generating active oxygen by acoustic cavitation caused by an ultrasonic wave.In WO98/01131, a method of reducing the threshold of cavitation by an amphophilic xanthene dye sensitizer and secondarily generating active oxygen by acoustic cavitation caused by an ultrasonic wave is proposed.

Kawabata et al. , in US Patent Application 20040044298, teaches us the use of a defocused ultrasonic wave that irradiates a large range including a diseased part is used in place of a focused ultrasonic wave. Therefore, a healthy tissue is hardly damaged by this defocused irradiation. The main ultrasonic wave influence is by the effect on medicine that remains in the disease region. Kawabata et al even suggest that this ultrasound source can be placed in a belt for home usage by the patient.

While Kawabata et al. approach is a major step in solving the low resolution problem of the "ultrasonic knife", we believe that by defocusing the ultrasound source it does not take full advantage of the concept of targeted medicine. It relies too much on the ability of the drug to affect only the malignant cells, and does not benefit from our ability to focus the ultrasonic energy to narrow targeted areas. Also relying on the patient ability to operate it seems to us as pushing this

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!UBSTITUTE SHEET(RULE26) concept too far, as most patients might be unable to treat themselves. It is also limited to specific organs that can be reached by using such a belt.

Tachibana at al, in US Patent application 20040059313, disclosed an Ultrasound kit for use with energy activated drugs. The kit includes a media with a light activated drug activated upon exposure to a particular level of ultrasound energy. The kit also includes a catheter with a lumen coupled with a media delivery port through which the energy activated drug can be locally delivered to the tissue site. The ultrasound transducer is configured to transmit the level of ultrasound energy which activates the energy activated drug with sufficient power that the ultrasound energy can penetrate the tissue site.

The delivery of energy activated drug to the tissue site can be through traditional systemic administration of a media including the energy activated drug or can be performed through localized delivery of the media. Localized delivery can be achieved through injection into the tissue

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!UBSTITUTE SHEET(RULE26) site or through other traditional localized delivery techniques. A preferred delivery technique is using a catheter which includes a media delivery lumen coupled with a media delivery port. The catheter can be positioned such that the media delivery port is within the tissue site or is adjacent to the tissue site via traditional over-the-guidewire techniques. The media can then be locally delivered to the tissue site through the media delivery port.

The localized delivery of the energy activated drug to the tissue sight serves to localize the energy activated drug within the tissue site and can reduce the amount of energy activated drug which concentrates in tissues outside the tissue site. Further, localized delivery of the energy activated drug can serve to increase the concentration of the energy activated drug within the tissue site above levels which would be achieved through systemic delivery of the energy activated drug. Alternatively, the same concentration of energy activated drug within the tissue site as would occur through systemic administration can be achieved by introducing smaller amounts of energy activated drug into a patient's body.

While the catheter is a good solution both for delivery of the photodynamic drug and for the ultrasonic generation, this solution is limited to large blood vessels and is still invasive in nature. The diameter of the catheter is quite big because of the ultrasonic transducer, and yet the transducer is too small for effectively focusing on the tissues that need treatment. Tachibana at al recommends inserting the catheter tip into the vasculature of the tumor. Again, this is limited to tumors that can be reached by a relatively thick intravascular catheter and to the stage when there is one tumor before cancer spreads to produce many small metastases sites. SUMMARY OF THE INVENTION

The present invention is directed to integrated systems and methods for performing a noninvasive therapeutic procedure of targeted and timed delivery of drugs to a target tissue inside the body, using extracorporeal acoustic or electromagnetic energy. More particularly, to systems and methods for affecting micro-bubbles that includes a energy activated drug activated upon exposure to ultrasound energy. Activation of the energy activated drug causes a disruption in the shell sufficient to cause a rupture of the microbubble. The microbubble further includes a therapeutic releasable from the microbubble upon rupture of the microbubble and yielding a therapeutic effect upon release from the microbubble.

Accordingly, noninvasive systems and methods for precise targeting and treating tissue region using extracorporeal focused energy, an ultrasonic imaging monitoring and ultrasound activated drugs would be useful.

!UBSTITUTE SHEET(RULE26) BRIEF DESCRIPTION OF TFIE DRAWINGS

Preferred embodiments of the present invention are illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings, in which like reference numerals refer to like components, and in which:

FIG. 1 is a simplified pictorial description of the integrated system three components: the ultrasonic imaging and control, the irradiating phased array for activating the drug and the drug delivery unit that delivers the microbubbles with the therapeutic agent.

!UBSTITUTE SHEET(RULE26) FIG. 2 is a cross-sectional detail of the ultrasonic transducer and target tissue region of FIG. 1. Microbubbles are accumulated in the tumor and rupture in a focal zone of the ultrasonic transducer.

FIG 3. which is a simplified pictorial description of an integrated delivery, imaging and therapeutic transducer

FIG 4 is a simplified pictorial description of another preferred embodiment, where electromagnetic microwave can be used to activate the energy activated drugs.

FIG 5. is a simplified pictorial description of the therapeutic procedure.

FIG 6. is a simplified pictorial description of transdermal administration of a drug the diagnostic procedure.

FIG. 7 is a simplified pictorial description of ultrasound imaging device that can monitor the accumulation and rupture of microbubble cloud in the target tumor site.

FIG 8 is a description of a Intra-cavitary application .

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention will be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which:

Reference is now made to FIG. 1, which is a simplified pictorial illustration of the proposed system and method for delivering and activating by extracorporeal focused ultrasound therapeutic agents within a tissue site. A patient 100 that has a tumor 102 is treated by the proposed system. An ultrasound transducer 140 in a degassed water container 130 is focusing ultrasonic energy at the target tumor tissue region 102 within the patient 100. The system includes a media 110 with a energy activated drug 112 activated upon exposure to a particular level and waveform of ultrasound energy irradiated from ultrasound transducer 140. The focused ultrasound includes a piezoelectric transducer 140, drive circuitry 152 coupled to the transducer for providing drive signals to the transducer, and a controller 154 coupled to the drive circuitry for controlling the intensity and wave shape of the drive signals. The ultrasound transducer is configured to transmit the level and wave form of ultrasound energy 142 which activates the energy activated drug accumulated in the tumor tissue 104 with sufficient power. Drug delivery using microbubbles can be by means of a systemic

1UBSTITUTESHEET(RULE26) application or local application. In the preferred embodiment, the energy activated drug in the form of microbubbles 112 is delivered by a transdermal applicator 110 using ultrasound energy, and controlled by controller box 150. The accumulated microbubbles cloud is monitored by ultrasound imaging through passed array probe 120, and control box 150. The whole system (Drug delivery, drug activation, and imaging) can be controlled through any microprocessor but is preferably done by a PC Notebook 160, through keyboard and touchpad / mouse 170 and the image is displayed on screen 180.

Reference is now made to FIG. 2 which is a simplified pictorial cross-sectional detail of the ultrasonic transducer 240 and target tissue region 200 (Designated as 102 in FIG. 1.) Microbubbles 204 are accumulated in the tumor 200 and rupture in a focal zone 250 of the ultrasonic transducer

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!UBSTITUTE SHEET(RULE26) 240. The focused ultrasound can employ various 1 -Dimensional, 1.5 Dimensional or 2 Dimensional phased arrays to achieve the focusing. In US patent application 20030187371, Vortman et al describe a system that employs focused ultrasound ablation using microbubbles . The disclosure of this patent application is hereby incorporated by reference. In this invention, we deliver microbubbles from outside (not shown I this pfigure) and use a focused ultrasound device 240, such as can be available from Insightec, Tirat Hacarmel, Israel, for the extracorporeal irradiation and bursting of the microbubbles 204, releasing their therapeutic content 206 in the targeted tissue 200. The controller 260 provides the control signals for transducer 240. The signals for the phased array can be pure sinus signals, as described by Ezion et al. US patent 6,506,154, or the signals described in Umemura et al patent 5,523,058, the disclosure of both patents is hereby incorporated by reference. As described in this prior art, certain wave shapes that correspond to frequency combinations can be more efficient than pure sine waves. E.g. a technique for switching a sound field at an interval of 0.01 to 10 milliseconds (ms) and radiating an ultrasonic wave is disclosed. According to this technique of switching sound fields, cavitation caused by one sound field is collapsed by the other sound field. Therefore, the efficiency of sonochemical reaction can be improved by an order of magnitude with the same ultrasonic power, compared with a case that sound fields are not switched. In our preferred embodiment, such frequency combinations are employed to achieve most efficient rupture of the microbubbles 206.

Reference is now made to FIG 3 which is a simplified pictorial description of a combined imaging and therapeutic transducer. Since we do not need high intensity focused ultrasound and not a very narrow focal zone, other transducers similar to those used in M mode in diagnostic ultrasound with a bit higher intensity can be employed. In US Patent Application 20040044298 by Kawabata et al, disclosure of which is hereby incorporated by reference, a defocused ultrasonic wave that irradiates a large range including a diseased part is used in place of a focused ultrasonic wave. Therefore, a healthy tissue is hardly damaged by this low intensity irradiation. The main ultrasonic wave influence is by the effect on medicine that remains in the disease region. An extracorporeal focused energy source, such as an ultrasonic 2-D Phased array source 300, can use directed to a targeted tissue site 310 which includes the energy activated drug 312. The targeted tissue 310 is then exposed to energy beams 320 from the energy source in order to activate any energy activated drug 312 within the tissue site. The activation of the energy activated drug causes rupture of the microbubbles and release of the therapeutic agent 314 within the tissue site. The same planar phased array 300 is used also for Ultrasound imaging. A beamformer 332 in the control box 330 produces the control signals for scanning beam for each row, and the receiver part 334 in the control box 330 provides the echo signals for producing "Echo-slice" 340. The received signals are processed by a PC, preferably, notebook PC, 350 and the image is displayed on the screen 360. The

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!UBf3TITUTESHEET(RULE26) PC imaging software can be any software used for medical ultrasound imaging but preferably it is a software that performs segmentation of objects and rendering, emphasizing the tumor 370 borders and the microbubbles cloud 380.

Reference is now made to FIG 4 which is a simplified pictorial description of another preferred embodiment, where electromagnetic microwave can be used to activate the energy activated drugs, as described in Tachibana et al US Patent 6,332,095, discloser of which is hereby incorporated by reference.- A method of treating abnormal cells, including cancer cells, includes administering a photosensitive chemical substance to accumulate at the cancer cell and applying a constant electric field or a high frequency electric field to the abnormal cells to thereby excite the photosensitive chemical substance to undergo a reaction detrimental to the abnormal cells. The abnormal cells may be in tissues inaccessible to light, including cancer cells in the blood. The electromagnetic field can

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!UBSTITUTE SHEET(RULE26) be applied by radiation through any media, but preferably through a dielectric wave guide, as depicted in FIG 4.

A patient 400 that has a tumor 402 is treated by the proposed system. An electromagnetic wave guide 440 in attached to the body through adaptor 430 is focusing electromagnetic energy at the target tumor tissue region 402 within the patient 400. The system includes a media 410 with a energy activated drug 412 activated upon exposure to a particular level and waveform of electromagnetic energy irradiated from electromagnetic waveguide 440. The focused electromagnetic includes a electromagnetic high frequency generator that is coupled to the body through a wave guide 440, drive circuitry 452 coupled to the transducer for providing drive signals to the wave guide, and a controller 454 coupled to the drive circuitry for controlling the intensity and wave shape of the drive signals. The electromagnetic source is configured to transmit the level and wave form of electromagnetic energy 442 which activates the energy activated drug accumulated in the tumor tissue 404 with sufficient power. Drug delivery using microbubbles can be done by means of a systemic application or local application. In the preferred embodiment, the energy activated drug in the form of microbubbles 412 is delivered by a transdermal applicator 410 using electromagnetic energy, and controlled by controller box 450. The accumulated microbubbles cloud is monitored by electromagnetic imaging through passed array probe 420, and control box 450. The whole system (Drug delivery, drug activation, and imaging) can be controlled through any microprocessor but is preferably done by a PC Notebook 460, through keyboard and touchpad / mouse 470 and the image is displayed on screen 480.

Reference is now made to FIG 5. , which is a simplified pictorial description of the therapeutic procedure. In one preferred embodiment of this invention, a low energy focused ultrasonic source 500 irradiates a set of focal points 510 that include a diseased part with ultrasound activated drugs. The irradiated focal point provides the necessary but not sufficient condition for the release of the therapeutic agent. Only cells that have the microbubbles 520 will be treated, so the suggested invention imposes a logical AND condition: a cell is affected by the treatment If and Only If both conditions are satisfied. Even if a part out of disease region is irradiated by an ultrasonic wave; a non-disease region 522 of a human body is hardly damaged because the intensity of the radiated ultrasonic wave is low. The effect of the irradiation of an ultrasonic wave on a disease region is small, and the therapeutic effect is mainly due to the effect of microbubbles burst and releasing the therapeutic agent. In accordance with one aspect of the present invention, a system is provided that includes a piezoelectric transducer 500, drive circuitry, and a controller 530. The drive circuitry is coupled to the transducer to provide drive signals to the transducer, causing the transducer to transmit acoustic energy, towards the set of focal zones 510. The controller is coupled to the drive

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!UBSTITUTE SHEET(RULE26) circuitry, and is configured for to provide the intensity and wave shape sufficient to cause collapse or cavitation of the microbubbles, without causing tissue coagulation and/or necrosis. A method for releasing a therapeutic 528 from a microbubble 524 is also disclosed. The method includes providing a microbubble with an energy activated drug activatable upon exposure to ultrasound energy source 500; and delivering ultrasound energy to the microbubble at a frequency and intensity which activates the energy activated drug to cause a rupture of the microbubble 524. The microbubble 524 includes a substrate defining a shell of the microbubble 526 and having a thickness permitting hydraulic transport of the microbubble.

The procedure starts by delivering the stabilized micro-bubbles 542 that contain the therapeutic agent to the target tissues 510. The delivery could be either systemic or local. In a systemic delivery (not shown), the micro-bubbles accumulate in the target tissue. Local application includes, but not limited to direct application through a needle or micro-tube probe, catheter that reaches the vicinity

of the target tissue threaded through blood vessels or, digestive track or airways, or a transdermal application as depicted in FIG 5. The focused ultrasound irradiation starts in different time lags after administration and is extracorporeal. Stabilized bubbles 524 having a diameter of 1 to 10 .mu.m can resonate with the frequencies of 1 to 10 MHz, which are generally used in ultrasonic diagnosis. When bubbles of this size are used, the effects of cavitation can be produced directly in the step of collapse without following the process including nucleation, growth and collapse. Thus, cavitation can be caused with a smaller quanity of ultrasonic energy. Based on such principle, stabilized bubbles are effective in lowering the threshold of cavitation, as described in Ultrasonics, vol. 26, pp. 280-285 (1988). The protein or surface active agent, which is the material forming the shell 526 of stabilized gas is generally known to interact with a lipophilic substance to form a complex. The medicinally active substance capable of generating active oxygen species is generally lipophilic, and the complex of the shell material with the medicinally active, lipophilic substance capable of generating active oxygen species via cavitation serves to allow cavitation to occur at a lower sound intensity owing to occurrence of the stabilized bubbles and, upon occurrence of cavitation, sever to generate active oxygen species owing to the presence of the medicinally active substance capable of generating active oxygen species via acoustic cavitation. Thus, when bubbles having a diameter of 1 to 10 .mu.m are used as stabilized bubbles and applied to blood vessels, the thrombolytic and other effects, or the effects of destructing nutrient vessels for a tumor tissue and thus preventing the feeding of the tumor tissue can be produced without relying upon a thrombolytic agent or tumor tissue blocking agent.

When the diameter of stabilized bubbles is smaller than 1 .mu.m, cavitation occurs via the above- mentioned steps of growth, resonance and collapse, hence the effect of causing cavitation immediately from the step of collapse cannot be produced, unlike the case where the diameter is 1 .mu.m or larger. However, by using stabilized bubbles as the nuclei shown in FIG. 1, it is possible to produce the effects of cavitation through the steps of growth, resonance and collapse, bypassing the step of nucleation, so that the ultrasound intensity necessary for cavitation is lower. Further, stabilized bubbles submicron in size are accumulated at a tumor site, so that a medicinal preparation for energy activated treatment capable of being accumulated at a tumor site and capable of lowing the threshold of cavitation can be obtained.

The ultrasonic irradiation method described in U.S. Pat. No. 5,523,058 and comprising superposing a fundamental wave and its second harmonic component on each other promotes the process of bubble growth, hence is suited for combination with stabilized bubbles submicron in size. According to a report by Delecki et al. (Ultrasound in Med. & Biol., vol. 23, pp. 1405-1412 (1997)), the microbubble ultrasonic contrast agent Albunex (registered trademark), which is known to be stably present in vivo only for several minutes, lowers the threshold of cavitation in vivo even at several hours after administration. The shell constituting Albunex (registered trademark) is made of

13 lϋBSTITUTESHEETCRUlM a denatured albumin and the possibility of the shell remaining as a remnant after disintegration of each bubble is high as compared with the possibility of its forming a small bubble like a surface active agent. This shell remnant is a protein aggregate and, by forming protein aggregates submicron in size, it is possible to lower the threshold of cavitation and cause them to accumulate at a tumor site.

In US Patent application 20040059313, which its disclosure is hereby incorporated by reference, Tachibana et al disclosed an Ultrasound kit for use with light activated drugs. The kit includes a media with a light activated drug activated upon exposure to a particular level of ultrasound energy. The gas to be enclosed in the internal space of the shell may be air or gases sparingly soluble in water. The substance capable of generating active oxygen species upon ultrasonic irradiation may be retained on the surface of the shell or within the shell.

The shell may have a spherical shell form with an outside diameter of not smaller than 0.1 .mu.m but not larger than 5 .mu.m. By using stabilized bubbles not smaller than 0.1 .mu.m but not larger

14 lUBSTITUTESHEETCRUlM⁾ than 1 .mu.m in outside diameter as the medicinal preparation, it is possible to accumulate them at a tumor site.

The material constituting the shell is preferably a protein, in particular a surface active protein. The surface active protein is not particularly restricted but may be any of those proteins which are low in toxicity to the living body. Albumin, LDL and hemoglobin, which are abundant in blood, are particularly desirable. In some uses, proteins which do not occur in blood but are highly capable of causing foaming, such as saponin and protein Z, also can form shells with ease, hence can be used as the shell materials.

A surface active agent may also be used as a shell-constituting material. The surface active agent is not particularly restricted but one low in toxicity to humans is suited for use, hence a phospholipid is desirably used. The emulsion includes a lipoid as a hydrophobic component dispersed in a hydrophilic phase. The hydrophobic component of the emulsion comprises a pharmaceutically acceptable triglyceride, such as an oil or fat of a vegetable or animal nature, and preferably is selected from the group consisting of soybean oil, safflower oil, marine oil, black current seed oil, borage oil, palm kernel oil, cotton seed oil, corn oil, sunflower seed oil, olive oil or coconut oil. Physical mixtures of oils and/or interesterfied mixtures can be employed. The preferred oils are medium chain length triglycerides having Csub.8-C.sub.10 chain length and more preferably saturated. The preferred triglyceride is a distillate obtained from coconut oil. The hydrophobic content of the emulsion is preferably approximately 5 to 50 g/100 ml, more preferably about 10 to about 30 g/100 ml and approximately 20 g/100 ml of the emulsion.

Water can be added to the emulsion to achieve the desired concentration of various components within the emulsion. Further, the emulsion can include auxiliary ingredients for regulating the osmotic pressure to make the emulsion isotonic with the blood. Suitable auxiliary ingredients include, but are not limited to, auxiliary surfactants, isotonic agents, antioxidants, nutritive agents, trace elements and vitamins. Suitable isotonic agents include, but are not limited to, glycerin, amino acids, such as alanine, histidine, glycine, and/or sugar alcohols, such as xylitol, sorbitol and/or mannitol. Suitable concentrations for isotonic agents within the emulsion include, but are not limited to, approximately 0.2 to about 8.0 grams/100 ml and preferably about 0.4 to about 4 grams/100 ml and most preferably 1.5 to 2.5 gram/100 ml.

A typical emulsion is prepared using the following technique. The triglyceride oil is heated to 50 degree -70 degree. Celsius. While sparging with nitrogen gas. The required amounts of stabilizer (e.g. egg yolk phospholipids), bile acid salt, alcohol (e.g. ethanol), antioxidant (e.g. .alpha. -to¬ copherol) and energy activated drug are added to the triglyceride while processing for about 5 to about 20 minutes with a high speed blender or overhead mixer to ensure complete dissolution or uniform suspension. In a separate vessel, the required amounts of water and isotonic agent (e.g. -glycerin) are heated to

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IUBSTITUTESHEETCRUIM the above temperature (e.g. 50.degree.-70.degree.) while sparging with nitrogen gas. Next, the aqueous phase is transferred into the prepared hydrophobic phase and high speed blending is continued for another 5 to 10 minutes to produce a uniform but coarse preemulsion (or premix). This premix is then transferred to a conventional high pressure homogenizer (APV Gaulin) for emulsification at about 8,000-10,000 psi. The diameter of the dispersed oil droplets in the finished emulsion will be less than 5 .mu.m, with a large proportion less than 1 .mu.m. The mean diameter of these oil droplets will be less than 1 .mu.m, preferably from 0.2 to 0.5 .mu.m. The emulsion product is then filled into borosilicate (Type 1) glass vials which are stoppered, capped and terminally heat sterilized in a rotating steam autoclave at about 121. degree. C. As discussed above, the energy activated drug can also be delivered to the body in a media which includes microbubbles. Suitable substrates for the microbubble include, but are not limited to, biocompatible polymers, albumins, lipids, sugars or other substances. U.S. Pat. Nos. 5,701,899 and 5,578,291 teaches a method for synthesizing microbubbles with a sugar and protein substrate and is

incorporated herein by reference. U.S. Pat. Nos. 5,665,383 and 5,665,382 teaches a method for synthesizing microbubbles with a polymeric substrate and is incorporated herein by reference. U.S. Pat. Nos. 5,626,833 and 5,798,091 teach methods for synthesizing microbubbles with a surfactant substrate and are incorporated herein by reference. A preferred microbubble has a lipid substrate. U.S. Pat. Nos. 5,772,929 teaches methods for synthesizing microbubbles with a lipid substrate. U.S. Pat. Nos. 5,776,429, 5,715,824 and 5,770,222 teach preferred methods for synthesizing microbubbles with a lipid substrate and a gas interior and are incorporated herein by reference.

Suitable microbubbles with a lipid substrate can be liposomes. The liposomes can be unilamellar vesicles having a single membrane bilayer or multilamellar vesicles having multiple membrane bilayers, each bilayer being separated from the next by an aqueous layer. A liposome bilayer is composed of two lipid monolayers having a hydrophobic "tail" region and a hydrophilic "head" region. The formula of the membrane bilayer is such that the hydrophobic (nonpolar) "tails" of the lipid monolayers orient themselves towards the center of the bilayer, while the hydrophilic "heads" orient themselves toward the aqueous phase. Either unilamellar or multilamellar or other types of liposomes may be used.

Although the energy activated drug can be included in many different types of liposomes, the following description discloses particular liposome compositions and methods for making the liposomes which are known to be "fast breaking". In fast breaking liposomes, the energy activated drug-liposome combination is stable in vitro but, when administered in vivo, the energy activated drug is rapidly released into the bloodstream where it can associate with serum lipoproteins. As a result, the localized delivery of liposomes combined with the fast breaking nature of the liposomes can result in localization of the energy activated drug in the tissues near the catheter. Further, the fast breaking liposomes can prevent the liposomes from leaving the vicinity of the catheter intact and then concentrating in non-targeted tissues such as the liver. Delivery of ultrasound energy from the extracorporeal irradiation source that is focal point follows the catheter can also serve to break apart the liposomes after they have been delivered from the catheter.

Reference is now made to FIG 6., which is a simplified pictorial description of transdermal administration of a drug. Transdermal administration through the skin or through intrra-cavitary administration is a localized administration of a selected energy activated drug encapsulated in microbubbles of suitable diameter and shell to a patient through the skin or cavity wall. After a period of time, the drug clears from most normal tissue and is retained to a greater degree in specific tissues. E.g. in case of a lipid, it will be in lipid rich regions such as the liver, kidney, tumor, and atheroma. Cancer imaging and therapy have involved the use of small molecules in the microbubbles shells, such as peptides, that bind to tumor cell surface receptors.

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IUBSTT As described by Tachibana et al in US patent 6,096,000, the disclosure of which is hereby incorporated by reference, an apparatus for creating holes in a biological tissue is disclosed. The apparatus 600 includes a housing which at least partially defines a fluid chamber 610 with fluid 620. The fluid chamber 610 including a tissue contact surface 630 which is configured to be positioned adjacent the biological tissue 640 and targeted tumor 642. An ultrasound delivery device 650 is positioned adjacent the fluid chamber and is configured to cavitate a fluid within the fluid chamber 610. A plurality of apertures 660 extend from the fluid chamber through the tissue contact surface. The apertures are sized to permit passage of the cavitated fluid 670 through the apertures 660.

Control Box 680 controls the delivery of the cavitated fluid 670 through aperatures 660 and through the skin to the targeted tissue 642. The accumulation of the microbubble in the target tumor 642 is continuously monitored by ultrasonic imaging probe 690, and displayed on PC Notebook 682

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1UBSTITUTESHEET(RULE26) screen as tumor image 684. This is done both for diagnostic imaging purpose and as a treatment, when the microbubbles rupture under the influence of extracorporeal radiation energy 692.

Reference is now made to FIG. 7 which is a simplified pictorial description of ultrasound imaging device that can monitor the accumulation and rupture of microbubble cloud in the target tumor site. The ultrasound probe 700 has a phased array 710. The phased array can be linear, convex or even concave for this application. The number of elements can be any number greater than 8, but preferably equal or greater than 128 for good imaging quality. The imaging probe can be separate or part of the irradiating transducer 712.The targeted tumor 740 accumulates microbubbles 742. Because of their inclusion of gaseous medium, these microbubbles are excellent reflectors of ultrasound energy and the reflected echoes 744 are picked by the imaging probe 7OO.The Control Box 730 includes both the beam forming unit 732 and the receiver unit 734. The signals can be processed by any medical ultrasound image processing software in PC 750, but preferably is processed by a software algorithms that does segmentation and edge detection, to emphasize the microbubble clouds and reconstruct the tumor 740 image, displaying the reconstructed image 760 on the PC display 752. The reconstructed microbubbles image 762 depicts the tumor shape and helps monitor the accumulation and rupture of the microbubbles.

Reference is now made to FIG. 8 which is a simplified pictorial description of a Intra-cavitary application . The three major components of the integrated system are as before:

The imaging probe, the drug delivery probe of the energy activated drug and the energy irradiating probe. As before, all three probes are controlled by the same control box. However, the shape of the three probes might change according to the target organ.

In this case we target intra-cavitary application. A patient 800 that has a tumor 802 that is close to an intra cavity of the body like in cases of treating the digestive track or reproductive organs. An ultrasound transducer 840 in a degassed water container 830 is focusing ultrasonic energy at the target tumor tissue region 802 within the patient 800.

Alternatively, the energy irradiating transducer 840 can be in the form of a rectal or vaginal probe or any shape convenient for approaching the targeted body region without a surgical operation. The system includes a media 810 with a energy activated drug 812 activated upon exposure to a particular level and waveform of ultrasound energy irradiated from ultrasound transducer 840. The focused ultrasound includes a piezoelectric transducer 840, drive circuitry 852 coupled to the transducer for providing drive signals to the transducer, and a controller 854 coupled to the drive circuitry for controlling the intensity and wave shape of the drive signals. The ultrasound transducer

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!UBSTITUTE SHEET(RULE26) is configured to transmit the level and wave form of ultrasound energy 842 which activates the energy activated drug accumulated in the tumor tissue 104 with sufficient power. Drug delivery using microbubbles can be by means of a systemic application or local application. In the preferred embodiment, the energy activated drug in the form of microbubbles 812 is delivered by a transdermal applicator 810 using ultrasound energy, and controlled by controller box 850. The dransdermal applicator can be shaped according to the organ that is needed to be reached. I.e. the transdermal applicator could be shaped as a rectal or vaginal probe or any shape that will allow to reach conveniently the vicinity of the target organ. The accumulated microbubbles cloud is monitored by ultrasound imaging through passed array probe 820, and control box 850. Again, the imaging probe can be adapted to the shape of the targeted organ as intra cavitary device. The whole system (Drug delivery, drug activation, and imaging) is controlled through any microprocessor but

20

!UBSTITUTE SHEET(RULE26) is preferably done by a PC Notebook 860, through keyboard and touchpad / mouse 870 and the image is displayed on screen 880.

EXAMPLE 1

The following Example describes the delivery of a energy activated drug to a tumor. Microbubbles are prepared including cisplatin and photofrin according to the methods disclosed in U.S. Pat. No. 5,770,222. Ultrasound energy is delivered at about 0.3 W/cm.sup.2 at a frequency of approximately 1.3 MHz for about 15 minutes.

EXAMPLE 2

An example of the tumor treatment using a therapeutic agent comprising stabilized bubbles with a protein constituting a shell of each bubble and serving as a carrier and hematoporphyrin dimer contained in the shell and to be used in combination with an ultrasound, and ultrasonic irradiation by the second harmonic superimposition technique is now described.

An example of the constitution of a therapeutic apparatus for carrying out the treatment with the therapeutic agent according to the invention in combination with an ultrasound is shown in FIG. 10. This treatment apparatus is constituted such that ultrasonic irradiation can be carried out by the second harmonic superposion technique so that an ultrasound with a fundamental frequency (fundamental waves) may superpose on an ultrasound with a double frequency (second harmonic waves) at the focus thereof. This second harmonic superposition technique is suited for use in causing cavitation. The apparatus is constituted such that sinusoidal signals are generated by signal generators 5 and 7 under the control of a therapeutic ultrasound controller 9 and amplified by amplifiers 6 and 8 and ultrasonic irradiation is carried out by applying an alternating voltage to a transducer 2 for fundamental waves and a transducer 3 for second harmonic waves. The ultrasonic irradiation is carried out via degassed water 14. The ultrasonic echo image obtained by a probe 4 for ultrasonic diagnosis under the control of a controller 11 for targeting is displayed, together with the relevant therapeutic guidance, on an image processor 10. Information concerning the high application voltage, the site of the focus and so forth is given to the therapeutic ultrasound controller 9 when the system controller 12 is controlled by means of the console panel 13.

As for the procedure of treatment, position adjustment is made according to imaging diagnosis using an ultrasonic diagnostic probe 4 for targeting so that the transducer 2 for fundamental waves and the transducer 3 for second harmonic waves may focus on the tumor 1. While controlling the

21

!UBSTITUTE SHEET(RULE26) therapeutic ultrasound controller 9 by the system controller 12 and thus confirming the site for therapy, a therapeutic ultrasound is irradiated. Since the cavitation threshold is high when the frequency is high and a frequency of not higher than 3 MHz is suited for practical use, a frequency of O. l to 1.5 MHz is desirably used for the fundamental wave and a frequency of 0.2 to 3 MHz for the second harmonic. The ultrasound intensity is changed within the range of 5 to 100 W/cm.sup.2 according to the site to be irradiated.

In this treatment, the therapeutic effect is mainly produced by cavitation upon ultrasonic irradiation and by oxidative destruction of such constituents of tumor cells as the cell membrane by active oxygen species generated by hematoporphyrin dimer upon cavitation. In addition, the contribution of the thermal effect resulting from absorption of the ultrasonic energy by the tissues can also be expected. In this therapy, the technique of superposing the fundamental wave and the second harmonic thereof on each other at the site of treatment for the purpose of causing cavitation at a

22

!UBSTITUTE SHEET(RULE26) lower energy level.

EXAMPLE 3

The following Example describes the delivery of a energy activated drug to a thrombosis. Microbubbles are prepared including heparin, photofrin and an albumin substrate. The microbubbles are systemically administered. Ultrasound energy is delivered from an extracorporeal focused source at about 0.2 W/cm.sup.2 in the focal point, at a frequency of approximately 1.3 MHz for about 20 minutes.

EXAMPLE 4

The following examples are for miniaturized systems that includes all the three components or part of them in one small unit. One embodiment is a device for dental application where a "toothbrush" delivers and activates the microbubbles. The "toothbrush" small device has a container filled with the microbubbles emulsion, as described in Tachibana at al, WO2004049964 .disclosure of which is hereby incorporated by reference.

Another miniaturized device is a transdermal application using a "Bio- Watch" device for active delivery of a drug, imaging and irradiating. The "Bio- Watch" has a disposable container of a drug, that is delivered transdermally by an ultrasonic transducer. The delivery rate can be displayed and microbubbles can be activated by the "Bio-watch" irradiation.

Yet another implementation is a transdermal application using a "Bio-Phone" mobile phone for delivery of the drug and activation of the energy activated drug. In this case, it can be done by using the mobile phone RF energy transmission for the activation. Such electromagnetic activation can activate microbubbles in a cosmetic or dermatology drug.

23

1UBSTITUTESHEET(RULE26)

Claims

1. A method for releasing a substance encapsulated in a microcapsule, comprising: delivering energy burstable microcapsules to a target tissue ; and delivering irradiated energy to the microcapsules from an extracorporeal energy irradiating source at a waveform and intensity which cause a rupture of the microcapsules in the targeted tissue.

2. The method of claim 1, wherein the microcapsules are microbubbles.

3. The method of claim 2, wherein the delivery of microbubles is systemic.

4. The method of claim 2, wherein the delivery of microbubles is orally.

5. The method of claim 2, wherein the delivery of microbubles is through intravenous infusion.

6. The method of claim 2, wherein the delivery of microbubles is local.

7. The method of claim 2, wherein the irradiating energy is ultrasound acoustic energy.

8. The method of claim 7, wherein the delivery of microbubles is transdermal.

9. The method of claim 7, wherein the delivery of microbubles is transdermal and assisted by energy.

10. The method of claim 7, wherein the delivery of microbubles is transdermal and assisted by energy, and both transdermal delivery and energy irradiation are controlled by the same controller.

11. The method of claim 10, wherein both transdermal ultrasound source and ultrasound irradiation are controlled by an ultrasound imaging.

12. The method of claim 6, wherein the delivery of microbubles is transcranial.

13. The method of claim 6, wherein the delivery of microbubles is transcranial and assisted by ultrasound energy.

14. The method of claim 13, wherein the delivery of microbubles is transcranial and assisted by ultrasound energy, and both transcranial delivery and ultrasound irradiation are controlled by the same controller.

15. The method of claim 14, wherein both transcranial ultrasound source and ultrasound irradiation are controlled by an ultrasound imaging.

16. The method of claim 6, wherein the delivery of microbubles is transspinal.

17. The method of claim 16, wherein the delivery of microbubles is trans spinal and assisted by ultrasound energy.

18. The method of claim 15, wherein the delivery of microbubles is transspinal and assisted by ultrasound energy, and both trans spinal delivery and ultrasound irradiation are controlled by the same controller.

19. The method of claim 16, wherein both trans spinal ultrasound source and ultrasound irradiation are controlled by an ultrasound imaging.

20. The method of claim 5, wherein the delivery of microbubles is through an intra-cavitary device.

21. The method of claim 18, wherein the delivery of microbubles is through the intra-cavitary device and assisted by ultrasound energy.

22. The method of claim 19, wherein the delivery of microbubles is through an intra-cavitary device and assisted by ultrasound energy, and both the intra-cavitay device delivery and ultrasound irradiation are controlled by the same controller.

23. The method of claim 20, wherein both the intra-cavitary device ultrasound source and ultrasound irradiation are controlled by an ultrasound imaging.

24. The method of claim 5, wherein the delivery of microbubles is done with a probe or needle to the targeted tissue.

25. The method of claim 15, wherein the delivery of microbubles is done with a probe or needle during laparoscopic surgery procedure.

25

!UBSTITUTE SHEET(RULE26)

26. The method of claim 7, wherein the delivery of microbubles is through a tube during an orthopedic surgery procedure.

27. The method of claim 5, wherein the delivery of microbubles is done with an externally operated swallowable capsule.

28. The method of claim 5, wherein the delivery of microbubles is through a microbubble spray inhalator.

29. The method of claim 19, wherein the delivery of microbubles in the spray and the ultrasonic delivery of the spray is controlled together with the ultrasound irradiation device.

30. The method of claim 6, wherein the delivery of microbubles is employed for dental purposes.

31. The method of claim 30, wherein the delivery of microbubles is done using toothpaste or mouth wash liquid, and energy is provided by a "toothbrush" like device.

32. The method of claim 1, wherein the microbubble is a liposome.

33. The method of claim 1, wherein the energy activated drug is the therapeutic agent.

34. The method of claim 1, wherein the microbubble includes the therapeutic in addition to the energy activated drug.

35. The method of claim 1, wherein the energy activated drug is coupled with a shell of the microbubble.

36. The method of claim 1, wherein the energy activated drug is enclosed within the microbubble.

37. The method of claim 1, wherein the energy activated drug is included in a media outside the microbubble.

38. The method of claim 1, for releasing a thrombolytic agent into a blood vessel, comprising: encapsulating the thrombolytic agent within a material formed at least in part of a energy activated drug; delivering the thrombolytic agent into the blood vessel; and emitting extracorporeal ultrasound energy at a waveform and intensity which activates the energy activated drug and thereby releases the thrombolytic agent from the material.

39. A microbubble, comprising: a substrate defining a shell of the microbubble and having a thickness permitting hydraulic transport of the microbubble; a energy activated drug activated upon exposure to extracorporeal irradiation of ultrasound energy, activation of the energy activated drug causing a disruption in the shell sufficient to cause a rupture of the microbubble; and a therapeutic releasable from the microbubble upon rupture of the microbubble to yield a therapeutic effect.

40. A system for performing a therapeutic procedure in a target tissue region of a patient, comprising: a transducer; drive circuitry coupled to the transducer for providing drive signals to the transducer such that the transducer transmits acoustic energy towards a focal

26

!UBSTITUTE SHEET(RULE26) zone; and a controller coupled to the drive circuitry, the controller configured for sequentially changing intensities and waveforms of the drive signals provided by the drive circuitry.

41. The system of claim 1, wherein the controller is configured for controlling the drive circuitry such that a duration of the drive signals at the intensity and waveform sufficient to causing microbubbles collapse

42. The system of claim 1, wherein the transducer comprises a multiple element transducer array, and wherein the controller is further configured for controlling a phase component of the drive signals to each element in the transducer array to at last partially focus the acoustic energy transmitted by the transducer at the focal zone.

43. The method of claim 31 wherein directing acoustic energy of a given intensity and waveform at the focal zone generates rupture of microbubbles in tissue in the focal zone without generating substantial rupture of microbubbles in tissue outside the focal zone.

44. The method of claim 1, when the ultrasonic irradiation for therapeutic use is installed in the patient bed.

45. The method of claim 1, where the ultrasonic irradiation for therapeutic use is replaced by electromagnetic high frequency energy.

46. The method of claim 1, when a high resolution image of the targeted area, made by Computed Tomography, MRI, PET etc. is fused with the image produced by the imaging system of the proposed system.

47. The method of claim 1, when the ultrasonic imaging system acquires the targeted zone and locks to it.

48. The method of claim 1, when the ultrasonic beam tracks the target zone when the targeted organ is moving.

49. The method of claim 1, where the high resolution tissue density data of the CT, MRI, etc.. is employed to correct aberrations in the focusing irradiating ultrasound.

50. A medicinal preparation which comprises a shell with a gas enclosed in the internal space thereof as well as a substance capable of generating active oxygen species upon irradiation of the shell with an extracorporeal ultrasound

51. A medicinal preparation as claimed in claim 1, wherein the shell has a spherical form with an outside diameter of not smaller than 0.1 .mu.m but not greater than 5 .mu.m.

52. A medicinal preparation as claimed in claim 1, wherein the material constituting the shell is a protein.

53. A medicinal preparation as claimed in claim 3, wherein the protein is a surface active protein.

54. A medicinal preparation as claimed in claim 3, wherein the protein is albumin, an LDL (low density lipoprotein), hemoglobin, saponin or protein Z.

55. A medicinal preparation as claimed in claim 1, wherein the material constituting the shell is a surface active agent.

56. A medicinal preparation as claimed in claim 2, wherein the substance capable of generating active oxygen species upon ultrasonic irradiation is selected from among photosensitizing antitumor agents, xanthene dyes and porphyrin dyes.

57. A carrier for carrying a medicinal component and to be used in combination with ultrasonic irradiation, wherein the carrier has a shell with an outside diameter of not smaller than

0.1 .mu.m but not greater than 5 .mu.m with a gas being enclosed within the inside thereof in a gaseous condition.

58. A method of producing medicinal preparations to be used in combination with ultrasonic irradiation comprising the steps of: forming foams or bubbles by irradiating a solution containing a surface active protein and a substance capable of generating active oxygen species upon ultrasonic irradiation; and selecting bubbles within a desired range of size from among the bubbles formed.

59. A tumor treatment method comprising the step of: administering, to a patient, a medicinal preparation comprising a shell not smaller than 0.1 .mu.m but not greater than 5 .mu.m in outside diameter with a gas enclosed within the inside and a substance capable of generating active oxygen species upon irradiation of the shell with an ultrasound; and irradiating the affected site of the patient with an ultrasound at a fundamental frequency and an ultrasound at the second-harmonic frequency relative to the fundamental ultrasound in the manner of superposition on each other.

60. A tumor treatment method as claimed in claim 10, wherein the fundamental wave has a frequency of 0.1 to 1.5 MHz.

61. An apparatus for releasing a substance encapsulated in a microcapsule, comprising: delivering energy burstable microcapsules to a target tissue ; and delivering irradiated

29

!UBSTITUTE SHEET(RULE26) energy to the microcapsules from an extracorporeal energy irradiating source at a waveform and intensity which cause a rupture of the microcapsules in the targeted tissue.

62. The apparatus of claim 61, wherein the microcapsules are microbubbles.

63. The apparatus of claim 62, wherein the delivery of microbubles is systemic.

64. apparatus of claim 62, wherein the delivery of microbubles is orally.

65. The apparatus of claim 62, wherein the delivery of microbubles is through intravenous infusion.

66. The apparatus of claim 62, wherein the delivery of microbubles is local.

67. The apparatus of claim 62, wherein the irradiating energy is ultrasound acoustic energy.

68. The apparatus of claim 67, wherein the delivery of microbubles is transdermal.

69. The apparatus of claim 67, wherein the delivery of microbubles is transdermal and assisted by energy.

70. The apparatus of claim 67, wherein the delivery of microbubles is transdermal and assisted by energy, and both transdermal delivery and energy irradiation are controlled by the same controller.

71. The apparatus of claim 70, wherein both transdermal ultrasound source and ultrasound irradiation are controlled by an ultrasound imaging.

72. The apparatus of claim 66, wherein the delivery of microbubles is transcranial.

73. The apparatus of claim 66, wherein the delivery of microbubles is transcranial and assisted by ultrasound energy.

74. The apparatus of claim 73, wherein the delivery of microbubles is transcranial and assisted by ultrasound energy, and both transcranial delivery and ultrasound irradiation are controlled by the same controller.

75. The apparatus of claim 74, wherein both transcranial ultrasound source and ultrasound irradiation are controlled by an ultrasound imaging.

76. The apparatus of claim 66, wherein the delivery of microbubles is transspinal.

77. The apparatus of claim 76, wherein the delivery of microbubles is trans spinal and assisted by ultrasound energy.

78. The apparatus of claim 75, wherein the delivery of microbubles is transspinal and assisted by ultrasound energy, and both trans spinal delivery and ultrasound irradiation are controlled by the same controller.

79. The apparatus of claim 76, wherein both trans spinal ultrasound source and ultrasound irradiation are controlled by an ultrasound imaging.

80. The apparatus of claim 65, wherein the delivery of microbubles is through an intra-cavitary device.

30

IUBSTITUTE SHEET(RULE2β)

81. The apparatus of claim 68, wherein the delivery of microbubles is through the intra-cavitary device and assisted by ultrasound energy.

82. The apparatus of claim 79, wherein the delivery of microbubles is through an intra-cavitary device and assisted by ultrasound energy, and both the intra-cavitay device delivery and ultrasound irradiation are controlled by the same controller.

83. The apparatus of claim 80, wherein both the intra-cavitary device ultrasound source and ultrasound irradiation are controlled by an ultrasound imaging.

84. The apparatus of claim 65, wherein the delivery of microbubles is done with a probe or needle to the targeted tissue.

85. The apparatus of claim 75, wherein the delivery of microbubles is done with a probe or needle during laparoscopic surgery procedure.

86. The apparatus of claim 67, wherein the delivery of microbubles is through a tube during an orthopedic surgery procedure.

31

!UBSTITUTE SHEET(RULE26)

87. The apparatus of claim 65, wherein the delivery of microbubles is done with an externally operated swallowable capsule.

88. The apparatus of claim 65, wherein the delivery of microbubles is through a microbubble spray inhalator.

89. The apparatus of claim 79, wherein the delivery of microbubles in the spray and the ultrasonic delivery of the spray is controlled together with the ultrasound irradiation device.

90. The apparatus of claim 66, wherein the delivery of microbubles is employed for dental purposes.

91. The apparatus of claim 90, wherein the delivery of microbubles is done using toothpaste or mouth wash liquid, and energy is provided by a "toothbrush" like device.

92. The apparatus of claim 61, wherein the microbubble is a liposome.

93. The apparatus of claim 61, wherein the energy activated drug is the therapeutic agent.

94. The apparatus of claim 61, wherein the microbubble includes the therapeutic in addition to the energy activated drug.

95. The apparatus of claim 61, wherein the energy activated drug is coupled with a shell of the microbubble.

96. The apparatus of claim 61 , wherein the energy activated drug is enclosed within the microbubble.

97. The apparatus of claim 61, wherein the energy activated drug is included in a media outside the microbubble.

98. The apparatus of claim 61, for releasing a thrombolytic agent into a blood vessel, comprising: encapsulating the thrombolytic agent within a material formed at least in part of a energy activated drug; delivering the thrombolytic agent into the blood vessel; and emitting extracorporeal ultrasound energy at a waveform and intensity which activates the energy activated drug and thereby releases the thrombolytic agent from the material.

99. A microbubble, comprising: a substrate defining a shell of the microbubble and having a thickness permitting hydraulic transport of the microbubble; a energy activated drug activated upon exposure to extracorporeal irradiation of ultrasound energy, activation of the energy activated drug causing a disruption in the shell sufficient to cause a rupture of the microbubble; and a therapeutic releasable from the microbubble upon rupture of the microbubble to yield a therapeutic effect.

100. A system for performing a therapeutic procedure in a target tissue region of a patient, comprising: a transducer; drive circuitry coupled to the transducer for providing drive signals to the transducer such that the transducer transmits acoustic energy towards a focal zone; and a controller coupled to the drive circuitry, the controller configured for

32

!UBSTITUTE SHEET(RULE26) sequentially changing intensities and waveforms of the drive signals provided by the drive circuitry.

101. The system of claim 1, wherein the controller is configured for controlling the drive circuitry such that a duration of the drive signals at the intensity and waveform sufficient to causing microbubbles collapse

102. The system of claim 1, wherein the transducer comprises a multiple element transducer array, and wherein the controller is further configured for controlling a phase component of the drive signals to each element in the transducer array to at last partially focus the acoustic energy transmitted by the transducer at the focal zone.

103. The apparatus of claim 31 wherein directing acoustic energy of a given intensity and waveform at the focal zone generates rupture of microbubbles in tissue in the focal zone without generating substantial rupture of microbubbles in tissue outside the focal zone.

104. The apparatus of claim 1 , when the ultrasonic irradiation for therapeutic use is installed in the patient bed.

33

IUBSTF

105. The apparatus of claim 1, where the ultrasonic irradiation for therapeutic use is replaced by electromagnetic high frequency energy.

106. The apparatus of claim I₅ when a high resolution image of the targeted area, made by Computed Tomography, MRI, PET etc. is fused with the image produced by the imaging system of the proposed system.

107. The apparatus of claim I₅ when the ultrasonic imaging system acquires the targeted zone and locks to it.

108. The apparatus of claim 1 , when the ultrasonic beam tracks the target zone when the targeted organ is moving.

109. The apparatus of claim I₅ where the high resolution tissue density data of the CT, MRI, etc.. is employed to correct aberrations in the focusing irradiating ultrasound.

110. A medicinal preparation which comprises a shell with a gas enclosed in the internal space thereof as well as a substance capable of generating active oxygen species upon irradiation of the shell with an extracorporeal ultrasound

111. A medicinal preparation as claimed in claim 1, wherein the shell has a spherical form with an outside diameter of not smaller than 0.1 .mam but not greater than 5 .mam.

112. A medicinal preparation as claimed in claim I₅ wherein the material constituting the shell is a protein.

113. A medicinal preparation as claimed in claim 3, wherein the protein is a surface active protein.

114. A medicinal preparation as claimed in claim 3, wherein the protein is albumin; an LDL (low density lipoprotein), hemoglobin, saponin or protein Z.

115. A medicinal preparation as claimed in claim I₅ wherein the material constituting the shell is a surface active agent.

116. A medicinal preparation as claimed in claim 2, wherein the substance capable of generating active oxygen species upon ultrasonic irradiation is selected from among photosensitizing antitumor agents, xanthene dyes and porphyrin dyes.

117. A carrier for carrying a medicinal component and to be used in combination with ultrasonic irradiation, wherein the carrier has a shell with an outside diameter of not smaller than 0.1 .mu.m but not greater than 5 .mam with a gas being enclosed within the inside thereof in a gaseous condition.

118. An apparatus of producing medicinal preparations to be used in combination with ultrasonic irradiation comprising the steps of: forming foams or bubbles by irradiating a solution containing a surface active protein and a substance capable of generating active oxygen species upon ultrasonic irradiation; and selecting bubbles within a desired range of size from among the bubbles formed.

34

1UBST ^ιIT7T^τ

119. A tumor treatment apparatus comprising the step of: administering, to a patient, a medicinal preparation comprising a shell not smaller than 0.1 .mu.m but not greater than

5 .mu.m in outside diameter with a gas enclosed within the inside and a substance capable of generating active oxygen species upon irradiation of the shell with an ultrasound; and irradiating the affected site of the patient with an ultrasound at a fundamental frequency and an ultrasound at the second-harmonic frequency relative to the fundamental ultrasound in the manner of superposition on each other.

120. A tumor treatment apparatus as claimed in claim 10, wherein the fundamental wave has a frequency of 0.1 to 1.5 MHz.

35

SfffiOT ITTf