Physical and biochemical stability of Optison, an injectable ultrasound contrast agent.

Optison(R) is an ultrasound contrast agent, consisting of gas-filled microspheres surrounded by a solid shell of heat-denatured human albumin. Size-distribution measurements of these microspheres are a critical stability indicating factor, because loss of encapsulated gas eliminates ultrasound contrast activity. Composition of the encapsulated gas is also critical, because air-filled microspheres do not persist nearly as long in vivo as microspheres filled with less soluble gases. Optison(R) stability has been tested during exposure to chemical substances expected to dissolve microsphere shells. In addition, size-distribution and gas-composition measurements were used to evaluate the effects of external gas composition, elevated temperature, mixing, needle shear and pressure on product stability. Optison(R) microsphere shells dissolve only when exposed to relatively extreme chemical conditions, such as low pH (<4.0), detergents or chaotropic salts. The shells are highly gas-permeable, and microspheres lose encapsulated gas rapidly and irreversibly when exposed to gas-deficient liquids. Pressure, impact stress, and the application of ultrasound energy all cause liquids to become gas-deficient, and also cause irreversible gas loss. Pressure sensitivity differs dramatically between mixed and unmixed microspheres, further supporting the conclusion that gas diffusion is the major cause of Optison(R) instability. To preserve the efficacy of Optison(R) as an ultrasound contrast agent, it is necessary to devote special attention to minimizing opportunities for gas exchange, mixing and exposure to gas-deficient liquids, so that the size distribution and gas composition of the original product are maintained during handling.