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Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragilityRelated Patent Categories: Surgery: Kinesitherapy, Kinesitherapy, UltrasonicMethod for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20050283098, Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This is a continuation of application Ser. No. 10/028,738, filed Oct. 22, 2001, which is a continuation-in-part of application Ser. No. 09/638,167, filed Aug. 11, 2000, of application Ser. No. 09/389,868, filed Sep. 2, 1999, and of application Ser. No. 09/245,781, filed Feb. 5, 1999, which in turn is a continuation-in-part of application Ser. No. 09/020,046, filed Feb. 6, 1998, now abandoned, the disclosures of which are all incorporated by reference herein in their entirety. FIELD OF INVENTION [0002] The current invention relates to a method of delivering a therapeutic agent to a localized region within a subject using ultrasound to trigger the release of the agent from hollow microbubbles having a specified set of mechanical properties. BACKGROUND OF THE INVENTION [0003] Ultrasound imaging has a wide application in the field of medical practice. Ultrasonic diagnostics refers to the imaging of a region of the human or animal patient using an ultrasound transducer to generate and receive ultrasound waves. Typically, the transducer is placed on the patient's body over the region to be imaged and high frequency sound waves are generated by the transducer and directed at the region. The transducer receives reflected ultrasonic waves from the region and converts the received waves into electrical signals from which an image is generated. Due to the extremely high acoustic reflectivity of gases, contrast agents comprised of gas bubbles with and without encapsulating shells are used to improve the quality of ultrasound images by highlighting the blood pool and the vascular perfusion of organs within the body. [0004] The use of ultrasound contrast agents serving also as drug carriers has been described for gas-filled liposomes in U.S. Pat. No. 5,580,575. A quantity of liposomes containing drug is administered into the circulatory system of a patient and monitored using ultrasonic energy at diagnostic levels until the presence of the liposomes are detected in the region of interest. Ultrasonic energy is then applied to the region that is sufficient to rupture the liposomes to release drugs locally for therapeutic purposes. The ultrasonic energy is described in U.S. Pat. No. 5,558,082 to be applied by a transducer that simultaneously applies diagnostic and therapeutic ultrasonic waves from therapeutic transducer elements located centrally to the diagnostic transducer elements. [0005] The use of gas-filled microcapsules to control the delivery of drugs to a region of the body has also been described in U.S. Pat. No. 5,190,766 in which the acoustic resonance frequency of the drug carrier is measured in the region in which the drug is to be released and then the region is irradiated with the appropriate sound wave to control the release of drug. Separate ultrasound transducers are described for the imaging and triggering of drug release in the target region. [0006] Exemplary contrast agents include, for example, stabilized microbubbles, sonicated albumin, gas-fulled microspheres, gas-filled liposomes, and gas-forming emulsions. A variety of methods have been developed for their manufacture. These methods usually involve spray drying, emulsion, or interfacial polymerization techniques. Typically, the result is a microbubble population having a range of diameters with either a fixed or an arbitrarily variable wall thickness. An ultrasonic contrast agent produced by one methodology, for example, may contain microbubbles where each has a shell wall of the same thickness regardless of its diameter. Alternatively, a different method of production may result in a microbubble population with wall thickness varying even between those microbubbles having the same diameter. [0007] Conceptually, for an ultrasound contrast agent to be used as a carrier for therapeutics, the agent would typically be, through processing, internally loaded with a drug. The treated microbubbles are then injected intravenously and allowed to circulate systemically. An ultrasound signal of sufficient energy to rupture the drug-containing microbubbles is applied to a region where the delivery of the drug is desired. The insonating beam destroys the microbubbles and thus releases its payload. [0008] An ultrasound contrast agent having a fuxed or an arbitrarily variable wall thickness may not by optimal as a carrier of therapeutic agent. A microbubble population having an arbitrary wall thickness could result in the drug being released prematurely or not at all. Those with thinner more fragile walls may rupture from hydrostatic pressure before reaching the site. Those with thicker more durable walls may not rupture at all. A microbubble population with a fixed wall thickness would similarly be unsuitable. While the strength of an encapsulated microbubble is a function of the thickness of its wall, it is also a function of its diameter. Thus, a relatively smaller microbubble would show more resistance to hydrostatic and acoustic pressures than would a relatively larger bubble having the same wall thickness. [0009] A drug-containing ultrasound contrast agent having a controlled fragility would therefore represent an improvement to the state of the art. For purposes herein, the term "controlled fragility" is taken to describe a microbubble population having the characteristic of being rupturable only when exposed to acoustic energy equal to or greater than a predetermined intensity. That is, below this acoustic intensity threshold, substantially all the microbubbles remain intact while above the acoustic intensity threshold the microbubbles rupture. While in the unruptured state, bubble agents can still be seen ultrasonically in the larger blood pool so that the sonographer can position and focus the scanner transducer on the region of interest prior to increasing ultrasound intensity to initiate agent rupture and concomitant delivery of drug. Thus, the agent can be turned-on or turned-off by controlling the intensity of the insonating signal. SUMMARY OF INVENTION [0010] The present invention provides a method of delivering therapeutic or diagnostic agents to a region of interest within a subject comprising the steps of introducing an agentloaded microbubble population having a controlled fragility into the bloodstream of the subject, directing at the region an insonating beam of ultrasound energy at a power intensity sufficient to induce rupture of the microbubbles and subsequent release of the active agent into the region to achieve therapeutic or diagnostic effect, and maintaining the power intensity until at least a substantial number of microbubbles are ruptured. The microbubble population has a controlled fragility characterized by a uniform wall thickness to diameter ratio that defines a discrete threshold power intensity value of ultrasonic energy where microbubble rupture in the population occurs. An advantage of the invention is that the microbubbles have specific and predetermined acoustic properties such that the specific ultrasound power intensity required to rupture the microbubbles can be predetermined as a release threshold prior to injection into the subject. In addition, microbubbles can be tailored for specific rupture characteristics to allow use of ultrasound conditions which will not cause rupture except in the desired body region. [0011] The method may also include the step of monitoring the location of the microbubbles by ultrasound or other suitable detection technique to detect their presence at the region of interest. [0012] Particularly preferred microbubbles will have a bi-layered shell having an outer layer of a biologically compatible amphiphilic material and an inner layer of a biodegradable polymer. Preferred threshold conditions for rupture are those at power, frequency, and waveform sufficient to provide a mechanical index from about 0.1 to about 1.9. BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIG. 1 is a plot of acoustic densitometry measured along the length of the flow phantom described in Example 1. [0014] FIG. 2 is a plot of fragility slope verses signal intensity described in the same experiment. [0015] FIG. 3 is a plot of acoustic densitometry decay curve measured according to Example 3. [0016] FIG. 4 is a plot of fragility slope v. mechanical index as described in Example 3. FIG. 5 is a plot of fragility slope v. intensity described in Example 7. DETAILED DESCRIPTION OF INVENTION [0017] The method for ultrasound triggered drug delivery according to the present invention relies upon an ultrasonic contrast agent consisting of a population of drug-carrying microbubbles having a controlled fragility which is derived from a specific and constant relationship between the microbubble shell thickness and its diameter. This relationship requires that, irrespective of diameter, the microbubbles exhibit an equivalent resistance to acoustic and hydrostatic stresses associated with an echographic imaging environment. [0018] Controlled fragility of a microbubble in drug release is an important consideration in localizing drugs with ultrasound. Microbubbles containing drugs should be resistant to rupture and inadvertent drug release by normal physiological pressures or by ultrasound conditions of the beam passing through tissues not at the target region. By normal physiological pressures, it is meant those pressures encountered in vivo including pressures within the heart and arteries, as well as compressive pressures of passing through constrictions such as capillaries. At minimum, in the use of microbubbles within the circulatory system, the microbubbles should be resistant to normal intracardiac pressures. For example, albumin microbubbles filled with air have been reported to "disappear" in significant amounts in the left ventricle (Gottlieb, et al., 1984), potentially causing problems in use as a drug delivery system to regions other than the left ventricle or with drugs with significant cardiotoxicity. Continue reading about Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility... Full patent description for Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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