Preliminary Safety Evaluation of Parenterally Administered Sulfoalkyl Ether β-Cyclodextrin Derivatives

• Published in: Journal of pharmaceutical sciences 1995-08, Vol.84 (8), p.927-932
• Main Authors: Rajewski, Roger A., Traiger, George, Bresnahan, James, Jaberaboansar, Parinaz, Stella, Valentino J., Thompson, Diane O.
• Format: Article
• Language: English
• Subjects: Animals; Anticoagulants - toxicity; Biological and medical sciences; Blood Urea Nitrogen; Chromatography, Thin Layer; Cyclodextrins - administration & dosage; Cyclodextrins - toxicity; Cyclodextrins - urine; Dextran Sulfate - toxicity; Drug toxicity and drugs side effects treatment; Erythrocytes - drug effects; Excipients - administration & dosage; Excipients - metabolism; Excipients - toxicity; Hemolysis - drug effects; Humans; In Vitro Techniques; Injections, Intraperitoneal; Kidney - pathology; Male; Medical sciences; Mice; Mice, Inbred Strains; Miscellaneous (drug allergy, mutagens, teratogens...); Partial Thromboplastin Time; Pharmacology. Drug treatments
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600840805

Parenteral administration of β-cyclodextrin (β-CD) results in renal and/or local toxicity dependent on the mode of administration. In an attempt to alleviate these properties, a series of anionically charged sulfoalkyl ether cyclodextrin (SAE-β-CD) derivatives have been developed. The parenteral safety of these derivatives was determined by survival of male mice after intraperitoneal (ip) injection, kidney histopathology, plasma urea nitrogen levels of mice determined 24h after injection, relativein vitrohemolytic potential and activated partial thromboplastin times (APTT). In addition, the 24-h renal excretion behavior of the derivatives was measured. Where appropriate, the results obtained with these cyclodextrin derivatives were compared with results obtained for β-CD and (hydroxypropyl)-β-cyclodextrin (HP-β-CD). The SAE-β-CD derivatives did not produce mortality in mice following ip injection at doses exceeding 5.45 mmol/kg. No significant histological lesions were observed in the kidney tissue of mice receiving the cyclodextrin derivatives. The SAE-β-CD derivatives were excreted faster and to a greater extent than β-CD and at rates comparable to HP-β-CD. The hemolytic potential of these derivatives was less than that of β-CD and comparable to or better than that of HP-β-CD. The SAE-β-CD derivatives did not increase APTT clotting times indicating that these derivatives have no significant anticoagulant activity. The toxicological profile of these derivatives suggests that these molecules may have application as biologically safe β-CD derivatives.