Booster for therapy of diseases with ultrasound and pharmaceutical liquid composition containing the same

#This invention relates to a booster useful for enhancing the effects of ultrasound in the therapy of various diseases and a pharmaceutical liquid composition containing the booster and a medicament which shows enhanced diffusion and penetration of the medicament into the body by applying ultrasound. More particularly, it relates to a booster useful for therapy of various disease by applying ultrasound which comprises a plurality of microbubbles of a gas in a liquid, a pharmaceutical liquid composition comprising a plurality of microbubbles of a gas and a medicament in a liquid, and the use thereof in the therapy of various diseases while applying ultrasound.

#It is known that various diseases are remedied by the aid of ultrasonic vibration. For example, it is described in Japanese Patent First Publication (Kokai) No. 115591/1977, etc. that percutaneous absorption of a medicament is enhanced by applying an ultrasonic vibration. Japanese Patent First Publication (Kokai) No. 180275/1990 discloses a drug-injecting device which is effective on the diffusion and penetration of the drug by applying an ultrasonic vibration in the step of injecting a drug into a human body via a catheter or a drug-injecting tube. U.S. Pat. Nos. 4,953,565 and 5,007,438 also disclose the technique of percutaneous absorption of medicaments by the aid of ultrasonic vibration. It is also reported that a tumor can be remedied by concentratedly applying ultrasound from outside the body.

#In order to enhance the therapeutic effects with ultrasound, it is required to apply a high energy ultrasonic vibration. However, ultrasonic vibration at an energy that is too high causes disadvantageously bums or unnecessary heat at the portion other than the desired portion. On the other hand, when the energy of an ultrasonic vibration is lowered for eliminating such disadvantages, there is a problem of less effect of the ultrasound at the desired portion.

#FIG. 1 shows a schematic view of one of the microbubbles contained in the booster of the invention.

#FIG. 2 shows a schematic sectional view of one embodiment of a drug administration device used for injecting, pouring, applying or circulating the booster or the pharmaceutical liquid composition of the invention.

#FIG. 3 shows a schematic sectional view of one embodiment of a drug administration device used for transdermal administration of the booster or the pharmaceutical liquid composition of the invention.

#The booster of the invention comprises a liquid containing a plurality of microbubbles of a gas having a diameter of 0.1 to 100 μm. The microbubbles are formed by entrapping microspheres of a gas into a liquid. The booster contains, for example, about 4×107 of the microbubbles per one milliliter of a liquid. The microbubbles are made of various gases such as air, oxygen gas, carbon dioxide gas, inert gases (e.g. xenon, krypton, argon, neon, helium, etc.), preferably air and oxygen gas. The liquid includes any liquid which can form microbubbles, for example, human serum albumin (e.g. 3 to 5% human serum albumin), a physiological saline solution, a 5% aqueous glucose solution, an aqueous indocyanine green solution, autoblood, an aqueous solution of maglumine diatriazoate (=renografin), and any other X-ray contrast medium.

#The booster can be prepared by a known method, for example, by agitating the liquid as mentioned above while blowing a gas as mentioned above into the liquid, or alternatively exposing the liquid to ultrasound with a sonicator under a gaseous atmosphere, whereby a vibration is applied to the liquid to form microbubbles of the gas.

#The pharmaceutical liquid composition of the invention comprises a plurality of microbubbles of a gas and a medicament in a liquid. The microbubbles of a gas and liquid are the same as mentioned above. The medicament includes any known medicaments effective for the desired therapy which can be absorbed percutaneously, for example, anti-thrombosis agents (e.g. urokinase, tissue plasminogen activator, etc.), hormones (e.g. insulin, etc.), theophylline, lidocaine, antibiotics, antineoplastic agents which are sensitive to ultrasound (e.g. doxorublein (=adriamycin), cytarabine (=Ara.C), etc.), and the like. The medicament can be contained in a therapeutically effective amount as usually used. The pharmaceutical liquid composition can be prepared by mixing a medicament with a booster comprising a plurality of microbubbles of a gas in a liquid. The mixing ratio may vary depending on the desired amount and kind of the medicament and the kind of the liquid, but is usually in a range of 1:100 to 100:1 by weight (a medicament/a booster).