Stabilization of Gas Bubbles Released from Water‐Soluble Carbohydrates Using Amphiphilic Compounds: Preparation of Formulations and Acoustic Monitoring of Bubble Lifetime

Abstract

The ultrasound contrast agents Echovist® and Levovist® (Bayer AG, Schering AG, Germany) are based on the release of gas bubbles from milled α-d-galactose. In diagnostic ultrasound, for this class of contrast agents, there is a need for prolonged contrast duration. To investigate if new carbohydrate compositions could prolong the lifetime of the gas bubbles, α-d-galactose was mixed with other carbohydrates or amphiphiles with varying log P. Acoustic attenuation vs. time (390 s) area under the curve (A 390) and bubble half-time (t½) were used as measures of prolonged lifetime of gas bubbles. The products, to which 0.1% of a lipophilic carboxylic acid (5β-cholanic acid, behenic acid, and melissic acid) has been added, showed more than 5, 7 and 11 times enhancement of A 390, respectively, compared with the reference compound 2 (RC2) corresponding to the commercial product Levovist®. The half-time t ½ of the same compounds was prolonged more than 6 times compared with RC2. A partial least square (PLS) statistical analysis confirmed that, for additives, high log P carboxylic acids lead to the highest A 390. The present results bear a promise of products with a more persistent in vivo ultrasound contrast effect than the commercially available agents.