Polyether-based bile acid sequestrants

Details Polyether-based bile acid sequestrants Polyether-based bile acid sequestrants

2000-11-15

2003-02-11

Dees, Jose' G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Solid synthetic organic polymer as designated organic active...

C424S400000, C424S484000, C424S486000, C424S487000

Reexamination Certificate

active

06517825

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 method for sequestering bile acids in a patient and to particular polymers for use in the method. The method comprises the step of administering to the patient a therapeutically effective amount of a polymer characterized by a polyether backbone and amino or ammonium groups pendant therefrom. The amino nitrogen atoms can be substituted by one or more substituents independently selected from among substituted and unsubstituted, normal, branched and cyclic alkyl groups, and aryl groups. When the polymer comprises pendant ammonium or quaternary ammonium groups, the polymer will be associated with a suitable anion, such as a conjugate base of a pharmaceutically acceptable acid.
The polymer to be administered can be a homopolymer or a copolymer. When the polymer is a copolymer, the polymer can comprise at least two distinct side chains.
The polymer can be linear, branched or crosslinked. In one embodiment, the polymer is crosslinked via the incorporation of a multifunctional comonomer. In another embodiment, the polymer is crosslinked via bridging groups which link amino nitrogen atoms on different polymer strands.
The invention further relates to a method for reducing blood cholesterol, treating atherosclerosis, treating hypercholesterolemia and/or reducing plasma lipid content of a mammal.
DETAILED DESCRIPTION OF THE INVENTION
The features and other details of the invention will now be more particularly described and pointed out 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 principal features of the invention can be employed in various embodiments without departing from the scope of the present invention.
In one aspect, the present invention relates to a method for sequestering bile acids in a patient and to particular polymers for use in the methods. The method comprises the step of orally administering to a mammal, such as a human, a therapeutically effective amount of a new class of polyether-based polymers comprising a polyether backbone having at least one amino or ammonium group pendant therefrom.
The invention also provides a method for reducing blood cholesterol, treating atherosclerosis, treating hypercholesterolemia and/or reducing plasma lipid content of a mammal. The methods comprises the step of orally administering to a mammal, such as a human, a therapeutically effective amount of a new class of polyether-based polymers comprising a polyether backbone having at least one amino or ammonium group pendant therefrom.
As used herein, the term “therapeutically effective amount” refers to an amount which is sufficient to bind bile acids, reduce blood cholesterol, treat atherosclerosis and/or treat hypercholesterolemia in a patient. The patient can be an animal, for example, a mammal such as a human.
In one embodiment, the polymer to be administered is characterized by a repeat unit of Formula I,
wherein n and m are each, independently, 0, 1 or 2 and p is 0 to about 6. R
1
, R
2
and R
3
are each, independently, a hydrogen atom; a substituted or unsubstituted, linear, branched or cyclic alkyl group; or a substituted or unsubstituted aryl group. Suitable alkyl and aryl substituents include aryl groups; halogen atoms, such as fluorine, chlorine, bromine and iodine atoms; alkyl groups; hydroxy; primary, secondary and tertiary amino; quaternary ammonium; alkoxy; carboxamido; sulfonamido; aryl; hydrazido; guanidyl; and ureyl. X
−
is a pharmaceutically acceptable anion. Examples of suitable anions include chloride, bromide, citrate, tartrate, lactate, methanesulfonate, acetate, formate, maleate, fumarate, malate, succinate, malonate, sulfate, hydrosulfate, L-glutamate, L-aspartate, pyruvate, mucate, benzoate, glucuronate, oxalate, ascorbate, acetylglycinate, the conjugate base of a fatty acid (e.g., oleate, laurate, myristate, stearate, arachidate, behenate, arachidonate) and combinations thereof. In a preferred embodiment, X
−
is chloride.
In one embodiment, at least one of R
1
, R
2
and R
3
is a hydrophobic group, preferably a hydrophobic alkyl group. “Hydrophobic group”, as the term is used herein, is a chemical group which, as a separate entity, is more soluble in octanol than water. For example, the octyl group (C
8
H
17
) is hydrophobic because its parent alkane, octane, has greater solubility in octanol than in water. The hydrophobic group can be a saturated or unsaturated, substituted or unsubstituted hydrocarbon group. Such groups include substituted and unsubstituted, normal, branched or cyclic alkyl groups having at least about four, preferably at least about six, carbon atoms, substituted or unsubstituted arylalkyl or heteroarylalkyl groups and substituted or unsubstituted aryl or heteroaryl groups. Preferably the hydrophobic group includes an alkyl group of between about four and thirty carbon atoms. More preferably the hydrophobic group includes an alkyl group of between six and about fourteen carbon atoms. Suitable hydrophobic groups include, for example, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-eicosyl. Other examples of hydrophobic groups include haloalkyl groups of at least about four, preferably about six, carbon atoms (e.g., 10-halodecyl), hydroxyalkyl groups of at least about four, preferably about six, carbon atoms (e.g., 11-hydroxyundecyl), and aralkyl groups (e.g., benzyl).
The polymer to be administered can also be characterized by a repeat unit of Formula I in which one of the substituents R
1
, R
2
and R
3
is absent. For example, when at least one of R
1
, R
2
and R
3
is a hydrogen atom, the repeat unit can also exist in the deprotonated basic form.
In one embodiment, the polymer to be administered is characterized by a repeat unit of Formula I wherein n is 1, m is 0 and p is 1. In this embodiment, the polymer can be, for example, an amino- or ammonium-substituted poly(epichlorohydrin) polymer.
The polymer to be administered can be a homopolymer or a copolymer. In one embodiment, the polymer is a copolymer characterized by two different repeat units of Formula I in which at least one of R
1
, R
2
and R
3
in the first repeat unit of Formula I differs from R
1
, R
2
or R
3
in the second repeat unit of Formula I. In another embodiment, the polymer is a copolymer characterized by a first repeat unit of Formula I and a second rep

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