| CLASSIFICATION | CommPat. Market |
| PATENT ASSIGNEE'S COUNTRY | USA |
| MARKETING BY | This data is not available for free |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 19.10.1999 |
| PATENT TITLE |
Hydrophobic sequestrant for cholesterol depletion |
| PATENT ABSTRACT |
The present invention relates to a poly(allylamine) polymer and, more generally, a hydrocarbon amine polymer. Preferably, these polymers are crosslinked. The present invention also relates to methods of forming these polymers and methods for their use. Further, the present invention relates to alkylating agents that can be employed to form the polymers and to methods for forming the alkylating agents. Generally, the polymer sequestrant includes a substituent bound to an amine of the polymer. The substituent includes a quaternary amine-containing moiety having one, two or three terminal hydrophobic substituents. A method of preparing quaternary amine-containing alkylating agents includes reacting an unsymmetrical dihalide with a tertiary amine having at least one hydrophobic substituent. A method for binding bile salts of bile acids in a mammal includes orally administering to the mammal a therapeutically-effective amount of the polymer sequestrant. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | November 3, 1998 |
| PATENT REFERENCES CITED |
Heming, A.E. and Flanagan, Thomas L., "Considerations in the Selection of Cation Exchange Resins for Therapeutic Use," Annals of the New York Academy of Sciences, 57:239-251 (1954). McCarthy, Peter A., "New Approaches to Atherosclerosis: An Overview," Medicinal Research Reviews, 13(2):139-159 (1993). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A hydrocarbon amine polymer, comprising a substituent bound to an amine of the hydrocarbon amine polymer, the substituent including a quaternary amine-containing moiety that is bound to said amine of the hydrocarbon amine polymer by an alkylene linking group having three or more carbons, said quaternary amine-containing moiety also including at least one terminal hydrophobic alkyl substituent, having between about 6 and 20 carbons. 2. The hydrocarbon amine polymer of claim 1, wherein the terminal hydrophobic alkyl substituent includes between about eight and twenty carbons. 3. The hydrocarbon amine polymer of claim 1, wherein the terminal hydrophobic alkyl substituent includes about ten carbons. 4. The hydrocarbon amine polymer of claim 1, wherein the terminal hydrophobic alkyl substituent includes about twelve carbons. 5. The hydrocarbon amine polymer of claim 1, wherein the terminal hydrophobic alkyl substituent includes about fourteen carbons. 6. The hydrocarbon amine polymer of claim 1, wherein said hydrocarbon amine polymer is crosslinked. 7. The hydrocarbon amine polymer of claim 6, wherein said hydrocarbon amine polymer includes a crosslinking moiety that is present in a range of between about 0.5 and twenty percent of amines of the polymer. 8. The hydrocarbon amine polymer of claim 6, wherein the crosslinking moiety is present in a range of between about 0.5 and six percent of amines of the polymer. 9. The hydrocarbon amine polymer of claim 1, wherein said hydrocarbon amine polymer is poly(vinylamine). 10. The hydrocarbon amine polymer of claim 1, wherein said hydrocarbon amine polymer is poly(ethyleneimine). 11. The hydrocarbon amine polymer of claim 1, wherein said hydrocarbon amine polymer is poly(allylamine). 12. A crosslinked poly(allylamine), comprising a substituent bound to an amine of the amine polymer, the substituent including a quaternary amine-containing moiety that is bound to said amine of the poly(allylamine) by an alkylene linking group having three or more carbons, said quaternary amine-containing moiety also including at least one terminal hydrophobic alkyl substituent, having between about 6 and 20 carbons wherein the poly(allylamine) is crosslinked by epichlorohydrin that is present in a range of between about 0.5 and six percent of the amines of the polymer. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION Salts of bile acids act as detergents to solubilize and consequently aid in digestion of dietary fats. Bile acids are derived from cholesterol and consequently, removing bile acids can result in reduction in 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 lost. 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 are consequently excreted. Many bile acid sequestrants, however, do not bind conjugated primary bile acids, such as conjugated cholic acid well enough to prevent substantial portions from being reabsorbed. In addition, the volume of sequestrants that can be ingested is limited. As a result, the effectiveness of many sequestrants to diminish blood cholesterol levels is also limited. Further, the synthesis of many sequestrants can be limited by the expense and reaction yield associated with preparing suitable precursors. For example, alkylating agents employed to modify polymers can be difficult to prepare. In addition, the ability of an alkylating agent to react with a polymer can also limit the effectiveness of the resulting sequestrant. A need exists, therefore, for a sequestrant and a method which overcomes or minimizes the referenced problems. SUMMARY OF THE INVENTION The present invention relates to a poly(allylamine) polymer and, more generally, a hydrocarbon amine polymer. Preferably, these polymers are crosslinked. The present invention also relates to methods of forming these polymers and methods for their use. Further, the present invention relates to alkylating agents that can be employed to form the polymers and to methods for forming the alkylating agents. In one embodiment, the poly(allylamine) polymer is crosslinked and comprises a substituent bound to an amine of the polymer. The substituent includes a quaternary amine-containing moiety, wherein a quaternary amine nitrogen of the moiety is bound to the amine of the polymer by an alkylene having three or more carbons and wherein at least one of three terminal substituents of the quaternary amine is a hydrophobic alkyl group having from six to about twenty-four carbons and the remaining terminal substituents are each independently alkyl groups having from one to about five carbons. The method for forming the crosslinked poly(allylamine) polymers includes reacting a crosslinked poly(allylamine) with a quaternary amine-containing compound having the formula ##STR1## wherein, R represents an alkyl group, at least one of which has from six to about twenty-four carbons and the remainder of which each independently have from one to about five carbons, n is an integer having a value of three or more, X is a leaving group, and Y is a negatively-charged counterion. In another embodiment, the present invention relates to a hydrocarbon amine polymer that includes a substituent bound to an amine of the polymer. The substituent includes a quaternary amine-containing moiety, wherein a quaternary amine nitrogen of said moiety is bound to the amine of the polymer by an alkylene having three or more carbons and wherein at least two of three terminal substituents of the quaternary amine are each a hydrophobic alkyl group having from six to about twenty-four carbons and the other terminal substituent is an alkyl group having from one to about five carbons. The method of forming a crosslinked hydrocarbon amine polymer of the invention includes the step of reacting a crosslinked hydrocarbon amine polymer with a quaternary ammonium compound having the formula ##STR2## wherein, R represents an alkyl group, at least one of which has from six to about twenty-four carbons and the remainder of which each independently have from one to about five carbons, n is an integer having a value of three or more, X is a leaving group, and Y is a negatively-charged counterion. Methods of use of the poly(allylamine) polymer and hydrocarbon amine polymers of the invention include their oral administration to a mammal in a therapeutic amount to bind bile salts, reduce blood cholesterol, treat atherosclerosis, treat hypercholesterolemia or reduce plasma lipid content of the mammal. In another embodiment, the invention is a quaternary ammonium compound having the formula ##STR3## wherein, R represents an alkyl group, at least one of which has from six to about twenty-four carbons and the remainder of which each independently have from one to about five carbons, n is an integer having a value of three or more, X is a leaving group, and Y is a negatively-charged counterion. A method of forming a quaternary ammonium compound includes the step of reacting a tertiary amine, having the formula ##STR4## wherein, R represents an alkyl group, at least one of which has from six to about twenty-four carbons and the remainder of which each independently have from one to about five carbons, with an unsymmetrical dihalide having the formula X.sup.1 --(CH.sub.2).sub.n --X.sup.2 wherein X.sup.1 is chloride, X.sup.2 is bromide, and n is an integer with a value of 3 or greater. This invention has many advantages. For example, the poly(allylamine) and hydrocarbon amine polymer sequestrants of the invention bind conjugated bile acids, including primary bile acids, that would otherwise be reabsorbed by active transport. One possible explanation for the improved performance of the polymer sequestrants of the invention in binding bile acids could be their ability to form both hydrogen and ionic bonds with bile acids. Hydrogen bonds can be formed by the secondary amine component of the polymer, while ionic bonds can be formed by the quaternary amine substituent. Further, the external, or terminal, distribution of hydrophobic components of the polymer sequestrants relative to the backbone of the polymer and relative to the secondary and quaternary amine components of the polymer can contribute to significantly increasing the effectiveness of each given dosage of sequestrant. In addition, the presence of two or more hydrophobic alkyl groups as terminal substituents ha the advantage of providing more sites for hydrophobic binding of the bile salts. The method of forming the polymer sequestrant of the invention also includes several advantages. For example, alkylation of an amine component of a hydrocarbon amine polymer, such as a poly(allylamine) polymer, with a quaternary amine can be facilitated by employing a quaternary amine that will be reactive with the amine component at a leaving group bearing-carbon atom that is at least three carbon atoms removed from the quaternary ammonium center. In addition, it is believed that performance of the resulting sequestrant can be improved as a consequence of employing an alkylene group of at least three carbons to bind the quaternary amine to an amine of a hydrocarbon amine polymer, and particularly to a poly(allylamine) polymer. Use of unsymmetrical dihalides in preparation of the quaternary amine-containing alkylating agents of the present invention can result in an increased yield and purity of desired product. Since the halogens in an unsymmetrical dihalide are not equivalent in reactivity, the carbon bearing the more reactive halogen will react almost exclusively, thereby forming a relatively pure compound in a good yield. This relatively pure quaternary amine-containing alkylating agent can then be used to alkylate an amine nitrogen of the hydrocarbon amine polymer backbone. 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 principle features of this invention can be employed in various embodiments without departing from the scope of the invention. A "hydrocarbon amine polymer," as that termed is employed herein, means a polymer consisting essentially of carbon, hydrogen and nitrogen. Preferably, the hydrocarbon amine polymer is crosslinked. More preferably, the hydrocarbon amine polymer is a poly(allylamine) polymer. Most preferably, the hydrocarbon amine polymer is a crosslinked poly(allylamine) polymer. Other examples of suitable hydrocarbon amine polymers include poly(vinylamine) and poly(ethyleneimine) polymers. The hydrocarbon amine polymer sequestrant of the invention includes a substituent bound to an amine of the polymer. The substituent includes a quaternary amine moiety, wherein the quaternary amine nitrogen of said moiety is bound to the amine of the polymer backbone by an alkylene having three or more carbons. At least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group having from six to about twenty-four carbons. The remaining terminal substituents are each independently alkyl groups having from one to about five carbons. A "terminal substituent" of the quaternary amine, as the term is employed herein, is any one of the three substituents on the quaternary amine nitrogen which is not the carbon chain between the amine on the polymer backbone and the amine of the quaternary ammonium center. A "hydrophobic alkyl group," as that term is employed herein, is an alkyl group having from six to about twenty-four carbons and which is terminated in a hydrophobic moiety. The hydrophobic alkyl group can be, for example, an aliphatic, aromatic, branches, or cyclic carbon chain. The hydrophobic substituent does not include the alkylene between the nitrogen of the amine polymer backbone and the nitrogen of the quaternary ammonium center. In one embodiment, the hydrocarbon amine polymer is a crosslinked poly(allylamine) polymer and comprises a substituent bound to an amine of the polymer. The substituent includes a quaternary amine-containing moiety, wherein a quaternary amine nitrogen of the moiety is bound to the amine of the polymer by an alkylene having three or more carbons and wherein at least one of three terminal substituents of the quaternary amine is a hydrophobic alkyl group having from six to about twenty-four carbons. The remaining terminal substituents are each independently alkyl groups having from one to about five carbons. Preferred embodiments include a crosslinked poly(allylamine) polymer wherein the alkylene is three carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which is either an octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Other preferred embodiments include a crosslinked poly(allylamine) polymer wherein the alkylene is four carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which is either an octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Another preferred embodiments include a crosslinked poly(allylamine) polymer wherein the alkylene is five carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which is either an octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Still other preferred embodiments include a crosslinked poly(allylamine) polymer wherein the alkylene is six carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which is either an octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. In one embodiment, poly(allylamine) polymer of the invention has the following general formula ##STR5## wherein, n has a value of three or more, and R represents an alkyl group, at least one of which has from six to about twenty-four carbons and the remainder of which each independently have from one to about five carbons. The method for forming the crosslinked poly(allylamine) polymers includes reacting a crosslinked poly(allylamine) with a quaternary amine-containing compound having the formula ##STR6## wherein, R represents an alkyl group, at least one of which has from six to about twenty-four carbons and the remainder of which each independently have from one to about five carbons, n is an integer having a value of three or more, X is a leaving group, and Y is a negatively-charged counterion. Preferred embodiments of the crosslinked poly(allylamine) formed by this method include a crosslinked poly(allylamine) polymer wherein the alkylene is three carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which is either an octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Other preferred embodiments of the crosslinked poly(allylamine) prepared by this method include a crosslinked poly(allylamine) polymer wherein the alkylene is four carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which is either an octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Additional preferred embodiments of the crosslinked poly(allylamine) formed by this method include a crosslinked poly(allylamine) polymer wherein the alkylene is five carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which is either an octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. Still other preferred embodiments of a crosslinked poly(allylamine) formed by this method, include a crosslinked poly(allylamine) polymer wherein the alkylene is six carbons in length, at least one of the three terminal substituents of the quaternary amine is a hydrophobic alkyl group which is either an octyl, decyl or dodecyl group and the remaining terminal substituents are methyl groups. In another embodiment, the present invention relates to a hydrocarbon amine polymer that includes a substituent bound to an amine of the polymer. The substituent includes a quaternary amine-containing moiety, wherein a quaternary amine nitrogen of said moiety is bound to the amine of the polymer by an alkylene having three or more carbons and wherein at least two or all three of the terminal substituents of the quaternary amine are each a hydrophobic alkyl group having from six to about twenty-four carbons. In the case where two of three terminal substituents of the quaternary amine are each a hydrophobic alkyl group, the other terminal substituent is an alkyl group having from one to about five carbons. In a preferred embodiment, the hydrocarbon amine polymer is crosslinked. The method of forming a crosslinked hydrocarbon amine polymer of the invention includes the step of reacting a crosslinked hydrocarbon amine polymer with a quaternary ammonium compound having the formula ##STR7## wherein, R represents an alkyl group, at least one of which has from six to about twenty-four carbons and the remainder of which each independently have from one to about five carbons, n is an integer having a value of three or more, X is a leaving group, and Y is a negatively-charged counterion. Preferred embodiments of the crosslinked hydrocarbon amine polymer formed by this method include, poly(vinylamine), poly(allylamine) and poly(ethyleneimine) polymers. Methods of use of the poly(allylamine) polymers and hydrocarbons amine polymers of the invention include their oral administration to a mammal in a therapeutic amount to bind bile salts, reduce blood cholesterol, treat atherosclerosis, treat hypercholesterolemia or reduce plasma lipid content of the mammal. Generally, a therapeutic amount of the hydrocarbon amine polymers or poly(allylamine) polymers, is an amount in a range of from about 0.1 grams/day to about twenty grams/day. In one embodiment, the method of the invention is a method for binding bile salts in a mammal, comprising the step of orally administering to the mammal a therapeutic amount of the hydrocarbon amine polymer of the invention. In another embodiment, the method of the invention is a method for binding bile salts in a mammal, comprising the step of orally administering to the mammal a therapeutic amount of the poly(allylamine) polymer of the present invention. In another embodiment, the invention is a method for reducing blood cholesterol in a mammal, comprising the step of administering to the mammal a therapeutic amount of the hydrocarbon amine polymer, preferably a crosslinked poly(allylamine) polymer, of the invention. In still another embodiment, the invention includes a method for treating atherosclerosis in a mammal, comprising the step of administering to the mammal a therapeutic amount of the hydrocarbon amine polymer, preferably a crosslinked poly(allylamine) polymer, of the invention. In still another embodiment, the method of the invention is that of treating hypercholesterolemia in a mammal, comprising the step of administering to the mammal a therapeutic amount of the hydrocarbon amine polymer, preferably a crosslinked poly(allylamine) polymer of the invention. Another embodiment of the invention is a method for reducing plasma lipid content of a mammal, comprising the step of orally administering to the mammal a polymer of the invention to tightly sequester conjugated bile acids secreted by the mammal, whereby a substantial portion of the conjugated bile acids are excreted by the mammal, thereby causing accelerated lipid metabolization and consequent lowering of plasma lipid content of the mammal. In a preferred embodiment, the sequestered conjugated primary bile acids include conjugated primary bile acids, such as conjugated cholic acid and conjugated chenodeoxycholic acid. The hydrocarbon amine polymers and poly(allylamine) polymers of this invention are particularly suitable for binding conjugated primary bile acids, such as glycocholic and glycochenodeoxycholic acids, in mammals by oral administration of the polymer. A particularly suitable form for oral administration of the hydrocarbon amine polymer and poly(allylamine) polymer is that which will form a gel in the stomach of a patient. Examples of suitable methods by which the preferred amine polymer of the invention can be formed are shown below: 1. One method involves polymerization of an amine monomer to form a homopolymer. Examples of this method include polymerization of allylamine, ethyleneimine, vinylamine, 1,2-diaminoethene, aminopropylacrylate, or p-aminomethylstyrene, to form their respective homopolymers. 2. Another method involves copolymerizing an amine monomer with one or more additional monomers. These additional monomers include amine monomers, such as those listed above, and non-amine monomers, such as acrylamide, styrene, divinylbenzene, vinyl alcohol, or vinyl chloride. Examples include copoly(allylamine/acrylamide), copoly(vinylamine/allylamine), and copoly(allylamine/divinylbenzene). 3. Still another method involves polymerization of a non-amine monomer to form a homopolymer that is subsequently chemically modified to form an amine polymer. Examples of this method include polymerization of vinyl formamide, vinyl acetamide, vinyl chloride, vinyl bromide, allyl chloride, allyl bromide, acrylamide, or acrylonitrile, to form their respective homopolymers. Each homopolymer would then be chemically altered to form an amine polymer using such reactions as hydrolysis, nucleophilic substitution, or reduction. The first four homopolymers listed above would then become poly (vinylamine) and the last four would become poly (allylamine). It is to be understood that not all of the initial non-amine monomer need be chemically altered, resulting in an amine polymer that contains some of the initial non-amine monomers in a non-amine state. 4. A fourth method involves copolymerizing a non-amine monomer with one or more additional monomers. These additional monomers could include amine monomers, such as those listed in the first method, and non-amine monomers, such as those listed in the third method. The resulting copolymer would then be chemically altered to form an amine polymer as in the third method. Examples would include copolymerization of acrylamide and styrene, followed by reduction to form copoly(allylamine/styrene), copolymerization of acrylonitrile and vinyl formamide, followed by reduction and hydrolysis, to form copoly (allylamine/vinylamine), and copolymerization of acrylonitrile and allylamine, followed by reduction, to form poly(allylamine). It is to be understood that not all of the initial non-amine monomer be chemically altered, resulting in an amine polymer that contains some of the initial non-amine monomers in a non-amine state. 5. A fifth method involves forming an amine polymer through a condensation mechanism. Examples of this method would include reaction of diethylenetriamine and epichlorohydrin, 1,3-dibromopropane and ethylenediamine, spermine and 1,4-butanediol diglycidyl ether, or tris(2-aminoethyl)amine and 1,10-dibromodecane. Each of these amine polymers typically has a molecular weight greater than about 2,000. Examples of resulting suitable hydrocarbon amine polymers include poly(vinylamine), poly(allylamine), and poly(ethyleneimine) polymers. A preferred hydrocarbon amine polymer is poly(allylamine) polymers. Preferably, the hydrocarbon amine polymer is crosslinked, such as by reacting the polymer with a suitable crosslinking agent. Examples of suitable crosslinking agents include acryloyl chloride, epichlorohydrin, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, dimethyl succinate, etc. Epichlorohydrin is a preferred crosslinking agent. Typically, the amount of crosslinking agent that is reacted with the hydrocarbon amine polymer is sufficient to cause between about 0.5 and twenty percent of the sites available for reaction to react with the crosslinking agent. In one preferred embodiment, between about 0.5 and six percent of the amine groups of a hydrocarbon amine polymer react with the crosslinking agent. In another preferred embodiment, between about two and about twelve percent of the amine groups of a hydrocarbon amine polymer react with the crosslinking agent. Crosslinking of the polymer can be achieved by reacting the polymer with a suitable crosslinking agent in an aqueous solution at about 25.degree. C. for a period of time of about eighteen hours to thereby form a gel. The gel is then combined with water or dried to form a particulate solid. The particulate solid can then be washed with water and dried under suitable conditions, such as a temperature of about 50.degree. C. for a period of time of about eighteen hours. The hydrocarbon amine polymer can be alkylated to form the sequestrants of the invention. An "alkylating agent," as that term is employed herein, means a reactant that, when reacted with a hydrocarbon amine polymer, causes the nitrogen atom of a quaternary amine-containing moiety to be covalently bound to one or more of the backbone amines of the hydrocarbon amine polymer by a alkylene having three or more carbons. Suitable alkylating agents of the present invention can be quaternary ammonium compounds. Therefore, in another embodiment, the invention is a quaternary ammonium compound having the formula ##STR8## wherein, R represents an alkyl group, at least one of which has from six to about twenty-four carbons and the remainder of which each independently have from one to about five carbons, n is an integer having a value of three or more, X is a leaving group, and Y is a negatively-charged counterion. In one embodiment, X is a halide. Preferably, the value of n is in a range of from three to six. In other embodiments, one or two of said alkyl groups is a methyl group. Particular examples of quaternary ammonium compounds suitable as alkylating agents include the following: (4-bromobutyl)dioctylmethylammonium bromide; (3-bromopropyl)dodecyldimethylammonium bromide; (3-chloropropyl)dodecyldimethylammonium bromide; (3-bromopropyl)octyldimethylammonium bromide; (3-chloropropyl)octyldimethylammonium bromide; (3-iodobutyl)dioctylmethylammonium bromide; (2,3-epoxypropyl)decyldimethylammonium bromide; (3-chloropropyl)decyldimethylammonium bromide; (5-tosylpentyl)dodecyldimethylammonium bromide; (6-bromohexyl)octyldimethylammonium bromide; (12-bromododecyl)decyldimethylammonium bromide; (3-bromopropyl)tridecylammonium bromide; (3-bromopropyl)docosyldimethylammonium bromide; (6-bromohexyl)docosyldimethylammonium bromide; (4-chlorobutyl)dodecyldimethylammonium bromide; (3-chloropropyl)octadecyldimethylammonium bromide; (3-chloropropyl)hexyldimethylammonium bromide; (3-chloropropyl)methyldioctylammonium bromide; (3-chloropropyl)methyldidecylammonium bromide; (3-chloropropyl)cyclohexyldimethylammonium bromide; (3-chloropropyl)tetradecyldimethylammonium bromide; etc. It is to be understood that the above compounds can be employed in halogenated forms including bromides, chlorides, and iodides as well as other negatively charged ions such as acetate, nitrate, sulfate, p-toluenesulfonate etc. An example of a suitable method by which the preferred quaternary ammonium compounds, useful as alkylating agents of the invention, can be formed includes the includes the steps of reacting a tertiary amine, having the formula ##STR9## wherein, R represents an alkyl group, at least one of which has from six to about twenty-four carbons, and the remainder of which each independently have from one to about five carbons, with an unsymmetrical dihalide having the formula X.sup.1 --(CH.sub.2).sub.n --X.sup.2 wherein X.sub.1 is chloride, X.sup.2 is bromide, and n is an integer with a value of 3 or greater. In other embodiments the tertiary amine can have two or all three alkyl or substituted alkyl groups having from six to about twenty-four carbons. In the case of two, the remaining alkyl group has from one to about five carbons. Typically, alkylation is accomplished by combining the substituted tertiary amine with a suitable dihalide in an organic solvent. An example of a suitable symmetric dihalide is a dichloride. An example of a preferred dichloride is 1,3 dichloropropane. Preferred dihalides of this invention also include unsymmetrical dihalides. "Unsymmetrical dihalides," as defined herein, are those dihalides wherein the halogens of the dihalide are not the same and consequently do not have the same reactivity as alkylating agents. Suitable examples of unsymmetrical dihalides include 1-bromo-3-chloropropane and 1-bromo-4-chlorobutane. Typically, when the dihalide is a bromide/chloride combination the bromide bearing end of the molecule is more reactive than the chloride bearing end of the molecule. Thus reaction of the unsymmetrical dihalide can result in almost exclusive reaction at the bromide bearing end leaving the chloride end unreacted. This relatively pure compound can then be used to alkylate the nitrogen of the hydrocarbon amine polymer, with reaction taking place at the chloride end. Use of the unsymmetrical dihalides increases both yield and purity of the resulting quaternary amine-containing alkylating agents, by avoiding undesirable side reactions which normally occur using symmetrical dihalides. Examples of suitable organic solvents include methanol, diethyl ether, etc. A preferred organic solvent is methanol. The reaction is maintained at a temperature and for a period of time sufficient to allow reaction of the tertiary amine with the unsymmetrical dihalide. These parameters are typically dependent on the nature of the reactants and can be determined by one of ordinary skill in the art using no more than routine experimentation. The reaction is terminated by removal of the solvent by suitable methods. The crude quaternary amine-containing alkylating agent is prepared for further reaction by methods known to those of ordinary skill in the art. The hydrocarbon amine polymer is typically alkylated by combining the polymer with the quaternary amine-containing alkylating agent in an organic solvent or water. The amount of the alkylating agent combined with the hydrocarbon amine polymer is generally sufficient to cause reaction of the alkylating agent with greater than about five percent of the reactive nitrogens on the hydrocarbon amine polymer. Examples of suitable solvents include methanol, ethanol, acetonitrile, water, etc. Preferred solvents are water and methanol. In a particularly preferred embodiment of the invention, the hydrocarbon amine polymer is a crosslinked poly(allylamine), wherein the substituent includes (3-propyl)dodecyldimethylammonium chloride. Alternatively, the hydrocarbon amine polymer is a crosslinked poly(allylamine), wherein the substituent includes butyldioctylmethylammonium chloride. Further, the particularly preferred crosslinked poly(allylamine) is crosslinked by epichlorohydrin that is present in a range of from about one-half and about six percent of the amines of the polymer. The hydrocarbon amine polymer of the invention can be subsequently treated or combined with other materials to form a composition for oral administration of the hydrocarbon amine polymer. The present pharmaceutical compositions are generally prepared by known procedures using well known and readily available ingredients. In making the compositions of the present invention, the hydrocarbon amine polymer can be present alone, can by admixed with a carrier, diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the polymer. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, syrups, aerosols, (as a solid or in a liquid medium), soft or hard gelatin capsules, sterile packaged powders, and the like. Examples of suitable carrier, excipients, and diluents include foods, drinks, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methyl cellulose, methylhydroxybenzoates, propylhydroxybenzoates, and talc. A negatively-charged counterion of the pharmaceutical composition can include organic ions, inorganic ions, or combinations thereof. Inorganic ions suitable for use in this invention include halide (especially chloride), carbonate and bicarbonate. Suitable organic ions include acetate and benzoate. The invention will now be further and specifically described by the following examples. All parts and percentages are by weight unless otherwise specified. EXAMPLE 1 Preparation of Poly(allylamine) Hydrochloride Crosslinked With Epichlorohydrin To a five gallon vessel was added poly(allylamine) hydrochloride (1 kg) obtained from Nitto Boseki and water (4 L). The mixture was stirred to dissolve the hydrochloride and the pH was adjusted by adding solid NaOH (284 grams). The resulting solution was cooled to room temperature, after which epichlorohydrin crosslinking agent (50 mL) was added all at once with stirring. The resulting mixture was stirred gently until it gelled (about thirty-five minutes). The crosslinking reaction was allowed to proceed for an additional eighteen hours at room temperature, after which the polymer gel was removed and placed in portions in a blender with a total of 10 L of water. Each portion was blended gently for about three minutes to form coarse particles which were then stirred for one hour and collected by filtration. The solid was rinsed three times by suspending it in water (10 L, 15 L, 20 L), stirring each suspension for one hour, and collecting the solid each time by filtration. The resulting solid was then rinsed once by suspending it in isopropanol (17 L), stirring the mixture for one hour, and then collecting the solid by filtration, after which the solid was dried in a vacuum oven at 50.degree. C. for eighteen hours to yield about 677 grams of the crosslinked polymer as a granular, brittle, white solid. |
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