Chad C. Huval

Biologically active polymeric sequestrants: Design, synthesis, and therapeutic applications

In recent years, functional polymers exhibiting inherently biological activities have been receiving increasing attention as polymer-based human therapeutic agents. These polymeric drugs exhibit unique pharmaceutical properties that are fundamentally different from their traditional small-molecule counterparts. However, unlike polymeric drug delivery systems, examples of polymers possessing intrinsically therapeutic properties are relatively scarce. By virtue of their high-molecular-weight characteristics, these polymeric drugs can be confined to the gastrointestinal (GI) tract, where they can selectively recognize, bind, and remove target disease-causing substances from the body. Being confined to the GI tract and non-biodegradable, these polymeric drugs are free from toxic effects that are associated with traditional systemic drugs. This report highlights recent developments in the rational design and synthesis of appropriate functional polymers that have resulted in a number of promising polymer-based therapeutic agents, including some marketed products.

Ammonium and Guanidinium Functionalized Hydrogels as Bile Acid Sequestrants: Synthesis, Characterization, and Biological Properties

Abstract Novel cationic polymers as bile acid sequestrants (BAS) have been considered to be an attractive long‐term therapy for the treatment of hypercholesterolemia. Due to the poor in vivo efficacy of the first generation of BAS like cholestyramine and colestipol, there is a need for discovering new generations of potent BAS. As part of our polymeric drug discovery efforts, we have developed a facile route to prepare functional hydrogels bearing pendant amine and guanidinium groups. The polymeric amines were prepared either by direct polymerization of amine containing monomers or by chemical modification of suitable polymeric precursors. Polymers bearing guanidinium groups were obtained by a polymer analog reaction on crosslinked polymeric amines (primary or secondary) using a readily available guanylating agent in aqueous medium. Incorporation of guanidinium groups to these polymers occurs under mild reaction condition. A numbers of polymer structures with pendant amine and guanidinium groups located at varying distances from the polymer backbone were obtained. These polymeric ammonium and guanidinium salts were evaluated in vivo as BAS and hence cholesterol lowering agents.

AMINE FUNCTIONALIZED POLYETHERS AS BILE ACID SEQUESTRANTS: SYNTHESIS AND BIOLOGICAL EVALUATION

A series of amine functionalized polymers based on polyether backbones was prepared by the chemical modification of poly(epichlorohydrin) and poly(2-chloroethylvinyl ether). Nucleophilic substitution of pendant chloroalkyl groups offers a versatile route to prepare hydrophilic, cationic polymers. Through the choice of appropriate experimental conditions, including solvent, temperature, and amine reagent, a high degree of substitution at the chloromethyl groups can be achieved. Depending on the nature of the amine used, both water-soluble and amphiphilic cationic polymers were obtained. Crosslinked hydrogels were prepared by either subsequent crosslinking of the amine functional polyethers or by reaction of chloroalkyl polyethers with multifunctional amines. These amine functional polyethers exhibited promising bile acid sequestration properties during in vivo experiments using hamsters as animal models, providing a novel approach for treating hypercholesterolemia. Some of these polymers show efficacy superior to commercially available bile acid sequestrants. The results suggest that these novel polyammonium gels may be useful as cholesterol lowering agents.

Three Generations of Bile Acid Sequestrants

Cholestyramine, the first bile acid sequestrant to be marketed, has been in use for over 20 years. Despite its low potency, requiring 16-24 g of polymer to achieve 20% LDL cholesterol reduction in hypercholesterolemic individuals, only one other sequestrant, colestipol, has come to market in the ensuing period. GelTex Pharmaceuticals has been involved for over six years in the discovery and development of new, more potent polymeric sequestrants. Two binding mechanisms are presented — one that operates via an aggregate binding structure and one that is effective via a defined site binding structure. These two binding mechanisms are compared and contrasted through bile acid binding isotherms. The best of these new sequestrants bind bile acids through a combination of hydrophobicity and ion exchange. Optimization and balancing of each of these interactions led us to more potent materials. The first of these, colesevelam hydrochloride is expected to be three to four times more potent than cholestyramine. A third generation product is still in research at GelTex. With another twofold increase in potency possible, single tablet therapy may become a reality.