Cardiovascular Effects of Selected Water-miscible Solvents for Pharmaceutical Injections and Embolization Materials: A Comparative Hemodynamic Study Using a Sheep Model

Abstract

Generally, organic water-miscible solvents are used intravascularly (both intravenously and intraarterially) for preparing two types of formulations, namely, pharmaceutical injections of poorly soluble drugs and precipitating liquid embolic polymeric materials for the minimally invasive treatment of aneurysms, arteriovenous malformations, or tumors, by arterial route. Although several of such solvents have been used in both drug delivery and interventional radiology, their safety profile is a concern. In particular, there is a lack of comparative investigations of their cardiovascular effects when injected intra-arterially.

We selected 13 non-aqueous water-miscible solvents based on their capacity to solubilize drugs or embolic polymeric materials, and on their described use, at least diluted with water, in pharmaceutical formulations. Their in vivo hemodynamic toxicity in male adult sheep after infra-renal aorta catheterization has been estimated with respect to the arterial and venous pressures, as well as the heart rate. Saline solution was used as a control. Three different volumes (0.1, 0.5, and 1.0 mL) were infused rapidly. An increase in arterial pressure and concomitant decrease in venous pressure, which we considered as signs of a cardiovascular toxicity, were observed to a differing extent for all organic solvents. Changes in heart rate were negligible.

Based on the intensity of arterial pressure change after a 1-mL infusion, a classification of the toxicity of the solvents following intra-arterial infusion is proposed:

• Solvents devoid of significant cardiovascular toxicity: dimethyl isosorbide (DMI), Glycofurol^TM 75, polyethylene glycol 200 (PEG 200), diglyme

• Solvents with moderate cardiovascular toxicity: tetrahydrofurfuryl alcohol (THFA), ethanol, acetone, Solketal^®, glycerol formal, dimethyl sulfoxide (DMSO)

• Solvents with marked cardiovascular toxicity: propylene glycol, ethyl lactate, N-methyl-2-pyrrolidone (NMP)

Emphasis is put on the relative character of the proposed ranking and on the lack for certain solvents, at least in the open literature, of data pertaining at other forms of toxic effects (e.g., undesirable pharmacological action, carcinogenicity, teratogenicity, mutagenicity, and irritating and sensitizing properties), all factors that have to be considered when selecting a proper solvent.