Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
1999-04-05
2003-08-26
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S078350, C514S824000
Reexamination Certificate
active
06610283
ABSTRACT:
BACKGROUND OF THE INVENTION
Salts of bile acids act as detergents to solubilize and, consequently, aid in the digestion of, dietary fats. Bile acids are derived from cholesterol. Following digestion, bile acids can be passively absorbed in the jejunum or reabsorbed by active transport in the ileum. Bile acids which are not reabsorbed 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, the blood cholesterol level can be reduced by hindering 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 are excreted. Serum cholesterol is then employed to produce more bile acids, thereby lowering the serum cholesterol level of the patient.
SUMMARY OF THE INVENTION
The present invention relates to a method for removing bile acids from a patient as well as certain 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 diallylamine monomer wherein the amino nitrogen atom bears at least one hydrophobic substituent. The hydrophobic substituent can be a substituted or unsubstituted, straight chain or branched C
3
-C
24
-alkyl group, a substituted or unsubstituted arylalkyl group or a substituted or unsubstituted aryl group. The polymer to be administered can be homopolymer or a copolymer.
In one embodiment, the polymer to be administered is a crosslinked or linear poly(diallylamine) polymer wherein at least 10% of the amino nitrogen atoms are substituted by a C
3
-C
24
-alkyl group. In another embodiment, the polymer to be administered is characterized by a diallylamine monomer wherein the amino nitrogen atom bears an alkyl group which is substituted with a quaternary ammonium group. The nitrogen atom of the ammonium group can bear at least one terminal hydrophobic substituent.
The polymer to be administered can comprise secondary amino groups, tertiary amino groups or quaternary ammonium groups or a combination thereof. Polymers which comprise secondary or tertiary amino groups can also be administered in the form of salts of a pharmaceutically acceptable acid.
The polymer can be linear 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.
In another embodiment, the invention relates to poly(diallylamine) polymers which are useful as bile acid sequestrants. These polymers are characterized by an diallylamine monomer, or repeat unit, wherein the amino nitrogen bears an alkyl substituent which is substituted with an ammonium group. The polymer can be a homopolymer or a copolymer.
The present invention offers the advantage that both substituted and unsubstituted diallylamines are readily polymerized and crosslinked, in comparison to other amine monomers. Such polymers also provide improved efficacy over polymers utilized in prior art methods.
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.
The present invention is based on Applicants' discovery that poly(diallylamine) polymers comprising hydrophobic groups exhibit excellent bile acid sequestration activity. The invention provides a method for removing bile acids from a patient comprising administering to the patient a therapeutically effective amount of a polymer characterized by a diallylamine monomer, or repeat unit, wherein the amino nitrogen atom bears a hydrophobic substituent.
As used herein, the term “therapeutically effective amount” refers to an amount which is sufficient to remove a significant quantity of bile acids from the patient and, thus, to lower the serum cholesterol level of the patient. The patient can be an animal, for example, a mammal, or a human.
A “hydrophobic substituent”, as the term is used herein, is a moiety which, as a separate entity, is more soluble in octanol than water. For example, the octyl (C
8
H
17
) group is hydrophobic because its parent alkane, octane, has greater solubility in octanol than in water. The hydrophobic substituent can be a saturated or unsaturated, substituted or unsubstituted hydrocarbon group. Such groups include substituted and unsubstituted, normal, branched or cyclic alkyl groups having 3 or more carbon atoms, substituted or unsubstituted arylalkyl or heteroarylalkyl groups and substituted or unsubstituted aryl or heteroaryl groups.
In one embodiment, the polymer to be administered is a poly(diallylamine) polymer characterized by a diallylamine monomer wherein the amino nitrogen atom bears at least one hydrophobic substituent selected from the group consisting of substituted or unsubstituted, normal, branched or cyclic C
3
-C
24
-alkyl groups, such as a hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl group; substituted or unsubstituted C
3
-C
24
-alkenyl groups, such as propenyl group; substituted or unsubstituted arylalkyl groups, such as a benzyl group; and substituted or unsubstituted aryl groups, such as a phenyl or naphthyl group. Suitable alkyl substituents include halo (e.g. fluoro, chloro, bromo or iodo) groups, and alkoxy, cycloalkyl, substituted and unsubstituted, quaternary, amido, sulfone, sulfoxide, alkoxy and aryl groups. Suitable aryl and arylalkyl substituents include fluoro, chloro, bromo, iodo, amino, ammonioalkyl, alkyl, alkoxy, hydroxy, alkoxy, sulfoxide and sulfone groups.
In one embodiment, at least 10% of the amino nitrogen atoms within the polymer to be administered bear a hydrophobic substituent, such as a C
2
-C
24
-alkyl group. Preferably at least about 20% of the amino nitrogen atoms bear a hydrophobic substituent. In other embodiments, at least about 40% of the amino nitrogen atoms can bear a hydrophobic substituent.
In general, poly(diallylamine) polymers are characterized by monomers, or repeat units, comprising five-membered rings, monomers comprising six-membered rings, or a combination thereof. In one embodiment, the polymer to be administered is characterized by an ammonium-bearing monomer of Formula I or of Formula II
or a combination thereof, wherein R
1
is a hydrophobic substituent, as described above, and R
2
is hydrogen, methyl, or a hydrophobic substituent. In a preferred embodiment, R
1
is selected from among the octyl, decyl and dodecyl groups and R
2
is methyl.
X
−
is an anion, such as the conjugate base of a pharmaceutically acceptable acid. Such anions include chloride, citrate, tartrate, lactate, phosphate, hydrophosphate, methanesulfonate, acetate, formate, maleate, fumarate, malate, succinate, malonate, sulfate, hydrosulfate, L-glutamate, L-aspartate, pyruvate, mucate, benzoate, glucuronate, oxalate, ascorbate and acetylglycinate. In a preferred embodiment, X
−
is chloride.
In another embodiment, the polymer to be administered is characterized by an amine-bearing monomeric unit of Formula III or Formula IV
or a combination thereof, wherein R is a hydrophobic substituent as previously described.
In a preferred embodiment, the polymer to be administered comprises one or more monomers of Formulas I-IV wherein at least 10%, preferably at least about 20%, of the amino nitrogen atoms bear a C
3
-C
24
-alkyl substituent. Examples of particularly preferred C
3
-C
24
-alkyl groups include hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl and tetradecyl groups.
The poly
Dhal Pradeep K.
Holmes-Farley Stephen Randall
Petersen John S.
Genzyme Corporation
Hamilton Brook Smith & Reynolds P.C.
Webman Edward J.
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