Alkylated poly(allylamine) polymers and methods of use

This application is a continuation of U.S. application Ser. No. 11/491,788, filed Jul. 24, 2006, which is a continuation of U.S. application Ser. No. 10/886,016, filed Jul. 7, 2004, now U.S. Pat. No. 7,101,960, which is a continuation of U.S. application Ser. No. 10/264,350, filed Oct. 3, 2002, now U.S. Pat. No. 6,784,254, which is a continuation of U.S. application Ser. No. 10/060,556, filed Jan. 30, 2002, now abandoned, which is a continuation of U.S. application Ser. No. 09/803,647, filed Mar. 9, 2001, now U.S. Pat. No. 6,433,026, which is a continuation of U.S. application Ser. No. 09/532,984, filed Mar. 22, 2000, now U.S. Pat. No. 6,225,355, which is a continuation of U.S. application Ser. No. 09/388,876, filed Sep. 2, 1999, now U.S. Pat. No. 6,066,678, which is a continuation of U.S. application Ser. No. 09/288,357, filed Apr. 8, 1999, now U.S. Pat. No. 5,981,693, which is a continuation of U.S. application Ser. No. 09/129,286, filed Aug. 5, 1998, now U.S. Pat. No. 5,917,007, which is a continuation of U.S. application Ser. No. 08/910,692, filed Aug. 13, 1997, now abandoned, which is a divisional of U.S. application Ser. No. 08/460,980, filed on Jun. 5, 1995, now U.S. Pat. No. 5,679,717, which is a continuation-in-part of U.S. application Ser. No. 08/258,431, filed Jun. 10, 1994, now abandoned. The entire teachings of all the above applications are hereby incorporated by reference.

This invention relates to removing bile salts from a patient.

Salts of bile acids act as detergents to solubilize and consequently aid in digestion of dietary fats. Bile acids are precursors to bile salts, and are derived from cholesterol. Following digestion, bile acids can be passively absorbed in the jejunum, or, in the case of conjugated primary bile acids, reabsorbed by active transport in the ileum. Bile acids which are not reabsorbed by active transport are deconjugated and dehydroxylated by bacterial action in the distal ileum and large intestine.

Reabsorption of bile acids from the intestine conserves lipoprotein cholesterol in the bloodstream. Conversely, blood cholesterol level can be diminished by reducing reabsorption of bile acids.

One method of reducing the amount of bile acids that are reabsorbed is oral administration of compounds that sequester the bile acids and cannot themselves be absorbed. The sequestered bile acids consequently either decompose by bacterial action or are excreted.

Many bile acid sequestrants, however, bind relatively hydrophobic bile acids more avidly than conjugated primary bile acids, such as conjugated cholic and chenodeoxycholic acids. Further, active transport in the ileum causes substantial portions of sequestered conjugated primary bile acids to be desorbed and to enter the free bile acid pool for reabsorption. In addition, the volume of sequestrants that can be ingested safely is limited. As a result, the effectiveness of sequestrants to diminish blood cholesterol levels is also limited.

Sequestering and removing bile salts (e.g., cholate, glycocholate, glycochenocholate, taurocholate, and deoxycholate salts) in a patient can be used to reduce the patient\'s cholesterol level. Because the biological precursor to bile salt is cholesterol, the metabolism of cholesterol to make bile salts is accompanied by a simultaneous reduction in the cholesterol in the patient.

Cholestyramine, a polystyrene/divinylbenzene ammonium ion exchange resin, when ingested, removes bile salts via the digestive tract. This resin, however, is unpalatable, gritty and constipating. Resins which avoid (totally or partially) these disadvantages and/or possess improved bile salt sequestration properties are needed.

The invention relates to the discovery that a new class of ion exchange resins have improved bile salt sequestration properties and little to no grittiness, thereby improving the palatability of the composition.

The resins comprise cross-linked polyamines which are characterized by one or more hydrophobic substituents and, optionally, one or more quaternary ammonium containing substituents.

In general, the invention features resins and their use in removing bile salts from a patient that includes administering to the patient a therapeutically effective amount of the reaction product of:

• • (a) one or more crosslinked polymers, salts and copolymers thereof characterized by a repeat unit selected from the group consisting essentially of: