John S. Petersen

Sevelamer, a Phosphate-Binding Polymer, is a Non-Absorbed Compound

ObjectiveTo examine the absorption, distribution and excretion of sevelamer hydrochloride in rats and humans.ParticipantsTwelve male Sprague-Dawley rats were used in the animal study, and twenty human volunteers participated in the clinical trial.MethodsIn the animal study, six rats received a single oral dose of [3H]sevelamer and six rats were pretreated with unlabelled sevelamer in the diet for 28 days followed by a single dose of [3H] sevelamer on day 29. Total urine and faeces were collected at intervals up to 72 hours post dose, and tissues were obtained at the time of sacrifice. In the clinical trial, subjects received a single oral dose of [14C]sevelamer following 28 days of pretreatment with unlabelled sevelamer. Blood, urine and faeces samples were collected at intervals up to 96 hours.ResultsIn the rat study, no significant urinary excretion of radioactivity was observed. The average recovery of radioactivity in the faeces was 98% in the single-dose group and greater than 100% in the group pretreated with unlabelled sevelamer for 28 days. A total of less than 0.1% of the dose was found in the tissues. In the human study, no detectable amount of 14C was found in the blood of any subject at any time. The majority of subjects had no detectable amounts of 14C recovered in the urine. In subjects where 14C was recovered in the urine, less than 0.02% was detected, a level equivalent to the free 14C detected in the [14C]sevelamer preparation. On average, greater than 99% of the administered dose was recovered in the faeces of the subjects.ConclusionThese studies demonstrate that sevelamer is a non-absorbed compound.

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.

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.

Hydrophobically Modified Poly(Allylamine) Hydrogels Containing Internal Quaternary Ammonium Groups as Cholesterol Lowering Agents: Synthesis, Characterization, and Biological Studies

Syntheses and physico-chemical characterization of a series of amphiphilic cationic hydrogels bearing pendant quaternary ammonium groups based on poly(allylamine) backbone are reported. These amphiphilic hydrogels were prepared by crosslinking soluble poly(allylamine) with epichlorohydrin followed by alkylation of the resulting gel with different functional alkyl chlorides bearing quaternary ammonium groups. Equilibrium swelling characteristics of these amphiphilic hydrogels were determined under a variety of solvent conditions. The roles of different parameters such as degree of crosslinking, degree of alkylation, and nature of alkylating agents on the swelling properties of these hydrogels were investigated. As part of a continuing structure-activity relationship study for the discovery of systemically non-absorbed cholesterol lowering agents, these amphiphilic hydrogels were also evaluated for their bile acid sequestration properties. Preliminary in vivo studies suggest these cationic hydrogels are potent bile acid sequestrants.