History, Chemical, and Pharmaceutical Development of Icodextrin

Abstract

Pharmaceutical formulations employing glucose as the osmotic agent in continuous ambulatory peritoneal dialysis (CAPD) have been available in the United Kingdom for some 15 years. They do, however, exhibit certain disadvantages related to the absorption of glucose through the peritoneum which have been well characterized. The development of possible alternatives such as dextran, amino acids, and glycerol is briefly reviewed. No commercially available products have emerged from this work. The use of a starch-based polyglucose as an alternative osmotic agent has also been the subject of clinical trials both in the United States and the United Kingdom. In the United States a narrow fraction low molecular weight product [molecular weight (MW) 1000 dalton] was extensively examined in dogs and patients. Disadvantages with high carbohydrate transference to the serum appear to have precluded its further development. In the United Kingdom a wider fraction based on an existing oral product, Caloreen, was first examined. This product had a bimodal MW distribution containing a fraction of MW 1000 dalton and another of MW 20000 dalton. These overlapping fractions were separated and the two component parts examined clinically. Surprisingly, the higher MW fraction showed most promise. The low MW fraction, virtually identical to the U.S. material, was rejected for the same reasons. The high MW material was purified, the critical aspects of its molecular size defined by the development of improved size exclusion chromatography techniques, and a new membrane manufacturing process established. The products made were extensively tested for toxicity and further examined clinically. A final product was selected and its specification defined. A multicenter clinical trial of the product, icodextrin, was conducted with excellent results. The importance of product control, especially with respect to MW, and the mode in which the osmotic effect occurs between virtually iso-osmolar solutions (colloidal osmosis) is emphasized. The development pharmacy and chemistry necessary to obtain a U.K. product license, now granted, is described.