Drug – bio-affecting and body treating compositions – Digestive system regulator containing solid synthetic...
Reexamination Certificate
1998-10-02
2001-09-25
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Digestive system regulator containing solid synthetic...
C424S078080, C424S078170, C424S078120, C424S078180, C424S078190, C424S078320
Reexamination Certificate
active
06294163
ABSTRACT:
BACKGROUND OF THE INVENTION
Biologically, cholesterol is eliminated from the body by conversion into bile acids and excretion as neutral steroids. Bile acids are synthesized from cholesterol in the liver and enter the bile as glycine and taurine conjugates. They are released in salt form in bile during digestion and act as detergents to solubilize and consequently aid in the digestion of dietary fats. Following digestion, bile acid salts are mostly reabsorbed by active transport in the ileum, complexed with proteins, and returned to the liver through hepatic portal veins. The small amount of bile acid salts not reabsorbed in the ileum is excreted via the distal ileum and large intestine, as a portion of the fecal material.
Therefore, reabsorption of bile acids, which can be present as the corresponding salts or conjugates, from the intestine conserves lipoprotein cholesterol in the bloodstream. As such, reducing reabsorption of bile acids within the intestinal tract can lower levels of bile acids circulating in the enterohepatic system thereby promoting replacement of bile acids through de novo synthesis from cholesterol, in the liver. The result is a lowering of circulating blood cholesterol levels.
One method of reducing the quantity of bile acids that are reabsorbed is the oral administration of compounds that sequester the bile acids within the intestinal tract and cannot themselves be absorbed. The sequestered bile acids consequently are excreted.
A need exists for sequestrants that bind bile acid salts and conjugates.
SUMMARY OF THE INVENTION
The present invention relates to a polymer composition comprising polymers containing a guanidinium moiety and to a method of using the guanidinium moiety-containing polymers for sequestering bile acids in a patient.
In one aspect, the guanidinium moiety is found within the backbone of the polymer. In this aspect, the polymer backbone comprises at least two atoms of the guanidinium group. In another aspect, the guanidinium moiety-containing polymer compositions comprise polymers with guanidinium substituents which are pendant from the backbone. For example, the polymer can comprise an aliphatic backbone bearing pendant guanidinium groups which can be further substituted.
In a particular embodiment, the pendant guanidinium substituent is a guanidinium derivative, for example, a cyclic structure wherein the imine nitrogen and the amine nitrogen of a guanidinium group are bonded by a C
2
-C
7
hydrocarbyl chain.
In another embodiment, the pendant guanidinium substituent can have a terminal nitrogen atom of the guanidinium group contained within the backbone of the polymer.
The polymer compositions comprising polymers with pendant guanidinium substituents can be prepared by reacting amine-containing polymers with guanylating agents, as described herein, thereby converting amines of said amine-containing polymers into guanidinium moieties.
In preferred embodiments, the guanidinium moiety-containing polymers can contain additional substituents which are bonded to available amine nitrogen atoms of said polymers. Amine nitrogen atoms which are available for substitution include the nitrogen atoms of primary, secondary or tertiary amines. These substituents can include a hydrophobic group such as a normal or branched alkyl group of at least about four carbon atoms, a quaternary ammonium-containing group such as an alkyltrialkyl ammonium group or combinations thereof. It is to be understood that the guanidinium group, the hydrophobic group and the quaternary ammonium-containing group when employed in any combination can be bonded to the same and/or different amine nitrogen atoms of the polymer.
Optionally the guanidinium moiety-containing polymers are crosslinked. Crosslinking is achieved by the incorporation of a multifunctional co-monomer into the polymer chains, or by means of a multifunctional crosslinking agent.
The method provided by the present invention comprises orally administering to a mammal a therapeutically effective amount of a guanidinium moiety-containing polymer composition, whereby, bile acids are sequestered and consequently excreted. The method of bile acid sequestration provided by the invention is useful to reduce the levels of circulating cholesterol, to treat atherosclerosis and/or to treat hypercholesterolemia. The method includes the administration of polymer compositions of the invention alone or in combination with one or more other antihyperlipoproteineimic or cholesterol lowering agents.
This invention provides many advantages over certain known bile acid sequestrants such as polyammonium salts which sequester bile acid salts through electrostatic interaction between the ammonium cations and the carboxylate and sulfonate anions of the bile acid salts. Guanidinium moiety-containing polymer compositions comprise guanidinium ions which are strong resonance-stabilized cations which remain charged and bind bile acid salts over a wider pH range than ammonium groups. Guanidinium ions form characteristic pairs of zwitterionic hydrogen bonds with carboxylate anions. This type of binding, which combines electrostatic interactions and hydrogen bonded structural organization, can lead to enhanced binding strength. Additionally, the combination of electrostatic and ionic hydrogen bonding ability can enable such guanidinium moiety-containing polymer compositions to be more selective anion receptors for carboxylate anions such as bile acid salts. Since increased binding strength and selectivity is indicative of increased efficacy, the guanidinium moiety-containing polymer compositions of the invention represent an improvement over certain known bile acid sequestrants.
DETAILED DESCRIPTION OF THE INVENTION
The features and other details of the invention will now be more particularly described and pointed out below as well as in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention.
The present invention relates to polymer compositions and to methods of using said compositions for removing bile acids from a patient. The polymer composition of the invention comprise guanidinium moiety-containing polymers and physiologically acceptable salts thereof. The precise nature of the polymeric backbone is not critical to the invention as the enhanced bile acid salt binding properties of the polymer compositions are, generally, due to the nature of the interaction of bile acid salts with the guanidinium moieties. Furthermore, additional substitution of guanidinium moiety-containing polymers with, for example, hydrophobic groups can also provide superior bile acid sequestrants.
In one aspect the guanidinium moiety-containing polymer composition comprises polymers wherein the backbone of the polymer comprises said guanidinium moiety. The backbone of these polymers comprise two or more atoms of the guanidinium group. The polymers can be made by polymerization of substituted carbodiimides such as those represented by Structural Formula (I):
R—N═C═N—R (I)
wherein R can be hydrogen, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a hydrophobic group or a quaternary ammonium-containing group. (See, for example, Heintz, A. M., and Novak, B. M.,
Polymer Preprints
, 39(2):429-430 (1998).)
Polymers of this type can comprise a repeat unit represented by Structural Formula (II):
wherein R can be as described above in Structural Formula I.
In another aspect the guanidinium moiety-containing polymer compositions comprise polymers with pendant guanidinium substituents. In one embodiment, the polymer can comprise an aliphatic backbone bearing pendant guanidinium substituents as represented in Structural Formula (III). In another embodiment a terminal nitrogen atom of the guanidinium group can be contained within the backbone of the polymer, as depicted in St
Dhal Pradeep K.
Holmes-Farley Stephen R.
Petersen John S.
GelTex Pharmaceuticals Inc.
Hamilton Brook Smith & Reynolds P.C.
Kulkosky Peter F.
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