Polymeric bile acid sequestrants—Synthesis using conventional methods and new approaches based on “controlled”/living radical polymerization

Abstract

a b s t r a c tPolymeric bile acid sequestrants have received increasing attention as therapeutic agents for the treatment of hypercholesterolemia. These materials are usually cationic hydrogels that selectively bind and remove bile acid molecules from the gastrointestinal tract, decreasing plasma cholesterol levels. Due to their high molecular weight, the action of bile acid sequestrants can be limited to the gastrointestinal tract, avoiding systemic exposure, which constitutes an advantage over conventional small-molecule drugs.Different polymers, such as vinyl polymers, acrylic polymers and allyl polymers have been used to prepare potential bile acid sequestrants based on conventional polymerization techniques. Also, much effort has been devoted to understanding the structure-property relationships between these polymers and their ability to bind bile acid molecules. The efficacy of these polymeric drugs can be ascribed to five major variables: (i) the density of cationic charges, (ii) the length and distribution of the hydrophobic chains, (iii) the polymer backbone flexibility, (iv) the degree of cross-linking and (v) the polymer shape.This review summarizes the major synthesis pathways that are employed in the preparation of this type of polymer therapeutics and the polymer structural key factors that are of relevance to enhanced therapeutic efficacy. Herein, new synthesis approaches, based on "controlled"/living radical polymerization techniques, are highlighted.

Novel bile acid sequestrant: A biodegradable hydrogel based on amphiphilic allylamine copolymer

“…In order to investigate the mechanism of the adsorption process, the pseudo-first-order model, the pseudo-second-order model, and the intraparticle diffusion model were used to explain the experimental data. The linear forms of the three kinetic models were expressed as equation (5), (6) and (7), respectively.…”

“…For example, the medications containing statins, nicotinic acid, and bile acid sequestrant (BAS) can control human CVD by reducing the elevated total cholesterol level and lower the density lipoprotein cholesterol level. [4][5][6] Among these chemical compounds, BAS is the only one which does not exhibit obvious systemic side effects and therefore is used as a common hypercholesterolemic drug since decades. 7,8 Moreover, BAS is an established therapeutic regimen also used for treating hypercholesterolemia with recognized safety owing to its biocompatibility and suitable mechanical properties.…”

“…The organism response leads to cholesterol consumption, which reduces the serum cholesterol levels. 6,[16][17][18] Polymeric BAS materials, are normally prepared from amine-containing polymer precursors, such as polyethylenimine, quaternized polystyrene, poly(vinylamine), and poly(allylamine) hydrochloride (PAH). 19 Because of the high chemical reactivity and excellent biocompatibility, PAH and its derivatives are used in many biological and medical fields, including drug-release, 20 gene therapy, 21 biomedical microencapsulation 22 , and heparin reversal.…”

“…Until now, the food and drug administration (FDA) approved the following three polymeric BAS using the above-mentioned polymer precursors cholestryamine, colestipol, and colesevelam hydrochloride. 6 Cholestryamine and colestipol are considered to be the first-generation of commercially available BAS, whereas colesevelam hydrochloride is more recent on the market. Cholestryamine is prepared from polystyrene via cross-linkage with divinylbenzene and subsequent quaternization, while colestipol is a condensation polymer containing secondary and tertiary amines.…”

Polymeric drugs: Advances in the development of pharmacologically active polymers

“…High cholesterol levels in the blood, especially high level of low-density lipoprotein (LDL) cholesterol, is associated with elevated risk of cardiovascular disease. Bile acids are effective targets for lowering the cholesterol since cholesterol is transformed into bile acids in the liver and clearance of bile acids promotes biosynthesis of more bile acids from circulating cholesterol to maintain normal levels [50, 80,81]. In contrast to ion sequestration where the binding mostly relies on electrostatic interactions and coordination bonding, organic small molecule substrates exhibit more structural complexity, making it possible to achieve higher binding affinity and specificity [52,54].…”