Internet for Pharmaceutical and Biotech Communities
| Newsletter | Advertising |
 
 
 

  

Pharm/Biotech
Resources

Outsourcing Guide

Cont. Education

Software/Reports

Training Courses

Web Seminars

Jobs

Buyer's Guide

Home Page

Pharm Patents /
Licensing

Pharm News

Federal Register

Pharm Stocks

FDA Links

FDA Warning Letters

FDA Doc/cGMP

Pharm/Biotech Events

Consultants

Advertiser Info

Newsletter Subscription

Web Links

Suggestions

Site Map
 

 
   



 

Title:  Methods of treating Syndrome X with aliphatic polyamines
United States Patent: 
7,261,880
Issued: 
August 28, 2007

Inventors: 
Burke; Steven K. (Sudbury, MA), Donovan; Joanne M. (Needham, MA)
Assignee: 
Genzyme Corporation (Cambridge, MA)
Appl. No.: 
10/125,701
Filed: 
April 17, 2002


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

The invention relates to a method for treating Syndrome X, or inhibiting the onset of symptoms of Syndrome X in a patient, and includes administering a therapeutically effective amount of a salt of at least one alkylated and cross-linked polymer, or a copolymer thereof, the polymer salt formed as a product of the reaction of one or more polymers, or salts and copolymers thereof, having a repeat unit that is essentially: ##STR00001## (see Original Patent). Long term administration of the cross-linked polyamine salts of the invention increases HDL levels and decreases LDL levels in patients. The invention also provides for administration of the polymer salt colesevelam, in combination with an HMG-CoA reductase inhibitor; the combined administration is effective in further lowering serum total-cholesterol and LDL-cholesterol levels beyond that achieved by either agent alone.

SUMMARY OF THE INVENTION

The present invention relates to the discovery that the long term administration of certain aliphatic polyamine polymers, such as colesevelam, increases HDL and decreases LDL levels in individuals. As such, one embodiment of the invention provides a method for treating Syndrome X by administering the aliphatic polyamine resins to the gastrointestinal tract of the patient.

One embodiment of the invention includes a treatment for Syndrome X in a human or nonhuman patient that exhibits one or more of the symptoms of Syndrome X, or that exhibits one or more of the symptoms of the metabolic disorders that characterize Syndrome X, by administering at least one polymer salt of the invention to the gastrointestinal tract. Another embodiment includes a prophylaxis or method of inhibiting the onset of the symptoms of Syndrome X, or method of inhibiting the onset of one or more of the symptoms of the metabolic disorders that characterize Syndrome X, by administering at least one polymer salt of the invention to the gastrointestinal tract.

According to an embodiment, a method for treating Syndrome X or inhibiting the onset of symptoms of Syndrome X in a patient includes administering to the gastrointestinal tract a therapeutically effective amount of the salt of at least one aliphatic amine polymer, such as an alkylated and/or cross-linked polymer, or a copolymer thereof, the polymer salt formed as a reaction product of the reaction of one or more polymers, or salts and copolymers thereof, having a repeat unit that is essentially (see Original Patent).

In a particular embodiment, the polymer salt that is administered includes a reaction product having: (i) at least some of the nitrogen atoms in the repeat units unreacted with the alkylating agent; (ii) less than 10 mol % of the nitrogen atoms in the repeat units reacting with the alkylating agent, forming quaternary ammonium units; and (iii) a fixed positive charge and one or more counterions, and wherein the alkylation of the polymer product is carried out prior to cross-linking.

A method for treating Syndrome X or inhibiting the onset of symptoms of Syndrome X in a patient, according to a particular embodiment includes administering a therapeutically effective amount of poly(allylamine hydrochloride) cross-linked with epichlorohydrin and/or alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide, wherein the polyallylamine is administered for a sufficient period of time to alleviate the symptoms of Syndrome X or to inhibit the onset of symptoms of Syndrome X.

In another embodiment, a method for treating the pathologies associated with Syndrome X or inhibiting the onset of symptoms of the pathologies associated with Syndrome X in a patient includes administering to the patient a therapeutically effective amount of the salt of at least one alkylated and cross-linked polymer, or a copolymer thereof, the polymer salt formed as a reaction product of the reaction of one or more polymers, or salts and copolymers thereof, having a repeat unit that is essentially (see Original Patent).  According to an embodiment, the polymer salt is administered for a sufficient period of time to alleviate the symptoms of the pathologies associated with Syndrome X or to inhibit the onset of symptoms of the pathologies associated with Syndrome X.

In one embodiment, the invention is a method for treating the pathologies associated with Syndrome X or inhibiting the onset of symptoms of the pathologies associated with Syndrome X in a patient, including administering to the patient a therapeutically effective amount of poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide, wherein the polyallylamine is administered for a sufficient period of time to alleviate the symptoms of the pathologies of Syndrome X or to inhibit the onset of symptoms of the pathologies of Syndrome X.

The method of the invention also includes administration of the polymer salt colesevelam, in combination with an HMG-CoA reductase inhibitor. The combined administration is effective in further lowering serum total-cholesterol and LDL-cholesterol levels beyond that achieved by either agent alone.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to the unexpected discovery that long term administration of certain polyamines, such as colesevelam, raises HDL levels in patients. This effect is relevant in an embodiment that includes the prophylaxis or treatment of Syndrome X and the pathologies associated with Syndrome X, an illness which is a combination of metabolic disorders, and which neither regresses spontaneously nor generally responds with any degree of long term success to conventional forms of treatment.

It was also discovered that, in the group of patients treated with one or more polymer salts according to an embodiment (polymer salt dose of 3.8 to 4.5 g/day), those patients having lower initial HDL's tend to have the greatest percent increases in HDL. This effect is illustrated graphically in FIG. 1.

It was further discovered that, in the group of patients treated with one or more polymer salts according to an embodiment (polymer salt dose of 3.8 to 4.5 g/day), those patients having relatively higher baseline triglycerides had the smallest increases in triglycerides. This effect is illustrated graphically in FIG. 2.

As described above, the preferred polymers employed in an embodiment of the method of the invention comprise water-insoluble, non-absorbable, preferably cross-linked polyamine polymer salts, such as aliphatic polyamines characterized by one or more hydrophobic substituents and/or one or more quaternary ammonium containing substituents.

In one embodiment, the polymer salt is characterized by 10 or more monomeric units and/or possesses a molecular weight of about 570 or more, preferably about 5,000 daltons or more.

Preferably the polymer salt is non-absorbable in the gastrointestinal tract and/or substantially water-insoluble. The terms "insoluble," "substantially water-insoluble," and grammatical variations thereof, as used herein, refer to a polymer or other substance which does not dissolve in an aqueous-based system, or which dissolves or solubilizes at a slower rate than does a water-soluble substance. Water-insoluble polymers introduced into the gastrointestinal tract are not absorbed systemically, or are absorbed to a lesser extent than are water-soluble polymers.

"Nonabsorbent" or "non-absorbable," as the terms are used herein, means that the polymer or other substance so described does not dissolve in the gastrointestinal tract, or dissolves to a lesser extent than does an absorbent or absorbable substance, or does not erode, degrade, or otherwise break down in vivo to form smaller chemical species by either physical or chemical processes. Therefore, a non-absorbable polymer is not absorbed systemically or is absorbed to a lesser extent than is an absorbable polymer. Accordingly, preferred reaction products of the invention include polymers that are cross-linked. A higher level of cross-linking decreases the water-solubility of the polymers, making them less absorbable, and thus substantially limits the activity of the alkylated, cross-linked polymers to the gastrointestinal tract only. Thus, because a highly cross-linked polymer of the invention is non-absorbable, the potential for undesirable side-effects in the patient is diminished.

"Alkylating agent," as the term is used herein, means a reactant which, when reacted with the cross-linked polymer, causes an alkyl group or derivative thereof (e.g., a substituted alkyl, such as an aralkyl, hydroxyalkyl, alkylammonium salt, alkylamide, or combination thereof) to be covalently bound to one or more of the nitrogen atoms of the polymer.

Suitable substituents for use in an embodiment include quaternary ammonium, amine, alkylamine, dialkylamine, hydroxy, alkoxy, halogen, carboxamide, sulfonamide and carboxylic acid ester, for example.

As described above, in one embodiment of the method, the polymer is administered in the form of a salt. As used herein, the term "salt" means that the nitrogen group in the repeat unit is protonated to create a positively charged nitrogen atom associated with a negatively charged counterion. A preferred polymer is a low salt, such as low chloride, form of polyallylamine where less than 40% of the amine groups are protonated.

The anionic counterions are selected to minimize adverse effects on the patient, as is more particularly described below. In a preferred embodiment, the counterion is selected to have a therapeutic benefit to the patient. Examples of suitable counterions include organic ions, inorganic ions, or a combination thereof, such as halides (Cl.sup.- and Br.sup.-), CH.sub.3OSO.sub.3.sup.-, HSO.sub.4.sup.-, SO.sub.4.sup.2-, HCO.sub.3.sup.-, CO.sub.3.sup.2-, acetate, lactate, succinate, propionate, oxalate, butyrate, ascorbate, citrate, dihydrogen citrate, tartrate, taurocholate, glycocholate, cholate, hydrogen citrate, maleate, benzoate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid. In one embodiment, the counterions are identical. In another embodiment, the counterions are different from each other. For example, a polymer salt according to one embodiment contains two different types of counterions.

Cross-linking

In a preferred embodiment, an amine polymer is cross-linked by means of a multifunctional cross-linking agent. A "multifunctional cross-linking agent," as that phrase is used herein, is a molecule containing two or more functional groups that can react with functional groups such as amine groups on polymers and form intramolecular or intermolecular chemical links between the chains of the polymers.

The polymers are preferably cross-linked prior to alkylation. Because of its high availability and low cost, epichlorohydrin is a preferred cross-linking agent according to an embodiment. Epichlorohydrin is also advantageous for use in an embodiment because of its low molecular weight and its hydrophilic nature, which increases the water-swellability and gel properties of the polyamine.

Other examples of cross-linking agents suitable for use in an embodiment include acryloyl chloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, and dimethyl succinate.

The amount of cross-linking agent used in an embodiment is typically between about 0.5% and about 25% (preferably between about 2.5% and about 20%; most preferably between about 1% and about 10%), based upon the combined weight of cross-linking agent and monomer.

Typically, the amount of cross-linking agent that is reacted with the amine polymer is sufficient to cause reaction of between about 0.5 percent and about twenty percent of the amine groups. In a preferred embodiment, between about 0.5 percent and about six percent of the amine groups react with the cross-linking agent.

Cross-linking of the polymer can be achieved by reacting the polymer with a suitable cross-linking agent in an aqueous caustic solution at about 25.degree. C. for a period of about eighteen hours to thereby form a gel. The gel is then combined with water and blended 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 about eighteen hours.

Alkylation

Alkylation involves reaction between the nitrogen atoms of the polymer and the alkylating agent (which may contain additional nitrogen atoms, e.g., in the form of amido or ammonium groups). In addition, the nitrogen atoms which do react with the alkylating agent(s) resist multiple alkylation to form quaternary ammonium ions such that less than 10 mol % of the nitrogen atoms have formed quaternary ammonium ions at the conclusion of alkylation.

The alkylating agents according to an embodiment are selected to provide hydrophobic regions and hydrophilic regions. In preferred embodiments, alkylating agents have the formula RX where R is a C1 C20 alkyl (preferably C4 C20), C1 C20 hydroxy-alkyl (preferably C4 C20 hydroxyalkyl), C7 C20 aralkyl, C1 C20 alkylammonium (preferably C4 C20 alkyl ammonium), or C1 C20 alkylamido (preferably C4 C20 alkyl amido) group and X includes one or more electrophilic leaving groups. As the phrase is used herein, "electrophilic leaving group" means a group that is displaced, during the alkylation reaction, by a nitrogen atom in the cross-linked polymer. Examples of preferred leaving groups include halide, epoxy, tosylate, and mesylate group. In the case of, e.g., epoxy groups, the alkylation reaction according to an embodiment causes opening of the three-membered epoxy ring.

Examples of alkylating agents according to preferred embodiments include a C1 C20 alkyl halide (e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decyl halide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, and combinations thereof); a C1 C20 dihaloalkane (e.g., a 1,10-dihalodecane); a C1 C20 hydroxyalkyl halide (e.g., an 11-halo-1-undecanol); a C1 C20 aralkyl halide (e.g., a benzyl halide); a C1 C20 alkyl halide ammonium salt (e.g., a (4-halobutyl) trimethylammonium salt, (6-halohexyl)trimethylammonium salt, (8-halooctyl)trimethylammonium salt, (10-halodecyl)trimethylammonium salt, (12-halododecyl)-trimethylammonium salts and combinations thereof); a C1 C20 alkyl epoxy ammonium salt (e.g., a (glycidylpropyl)-trimethylammonium salt); and a C1 C20 epoxy alkylamide (e.g., an N-(2,3-epoxypropane)butyramide, N-(2,3-epoxypropane) hexanamide, and combinations thereof).

In a preferred embodiment, the polymer is reacted with at least two alkylating agents, added simultaneously or sequentially to the polymer. In one preferred embodiment, for example, one of the alkylating agents has the formula RX where R is a C1 C20 alkyl group and X includes one or more electrophilic leaving groups (e.g., an alkyl halide), and the other alkylating agent has the formula R'X where R' is a C1 C20 alkyl ammonium group and X includes one or more electrophilic leaving groups (e.g., an alkyl halide ammonium salt).

In a particular embodiment, one of the alkylating agents has the formula RX and is a C10 alkyl halide, and the other alkylating agent has the formula R'X and is a C6 alkyl halide trimethyl ammonium salt.

In another preferred embodiment, one of the alkylating agents has the formula RX where R is a C1 C20 alkyl group and X includes one or more electrophilic leaving groups (e.g., an alkyl halide), and the other alkylating agent has the formula R'X where R' is a C1 C20 hydroxyalkyl group and X includes one or more electrophilic leaving groups (e.g., a hydroxy alkyl halide).

In another preferred embodiment, one of the alkylating agents is a C1 C20 dihaloalkane and the other alkylating agent is a C1 C20 alkylammonium salt.

The reaction products according to an embodiment are cations having fixed positive charges; these cations attract and acquire negatively charged counterions upon ingestion. According to another embodiment, the reaction product is provided with one or more counterions, and is essentially neutral in charge. The counterions, whether acquired when ingested or provided in the product-forming reaction, can be exchanged with ions of bile salts. Examples of counterions suitable for use in an embodiment are provided above. In one embodiment of the method, the polymer salt administered contains two different types of counterions, both of which are exchanged for bile salts. The result of the exchange of counterions for ions of bile salts is that, during long term administration of the polymer salt, the bile salts are removed from the gastrointestinal tract. In another embodiment, more than one reaction product, each having different counterions associated with the fixed charges, are administered.

In another embodiment the reaction products have the capability of becoming positively charged upon ingestion at physiological pH. The charged ions, upon their formation, attract and acquire negatively charged counterions. According to an embodiment, the acquired counterions are exchanged with ions of bile salts, thereby removing the bile salts from the gastrointestinal tract.

The amine polymer is typically alkylated according to a method of the invention by combining the polymer with the alkylating agents in an organic solvent. A preferred organic solvent for use in an embodiment is methanol. Examples of other organic solvents suitable for use in an embodiment include ethanal, isopropanol, acetonitrile, dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

In one embodiment, the alkylating agent is added to the cross-linked polymer at a molar ratio between about 0.05:1 and about 4:1. According to an embodiment, the amount of first alkylating agent combined with the amine polymer is generally sufficient to cause reaction of the first alkylating agent with between about 5 percent and about 75 percent of amine groups on the amine polymer that are available for reaction. The amount of second alkylating agent combined with the amine polymer and solution is generally sufficient to cause reaction of the second alkylating agent with between about 5 percent and about 75 percent of the amine groups available for reaction on the amine polymer.

In one embodiment, the reaction mixture is heated over a period of about forty minutes to a temperature of about 65.degree. C., with stirring. According to a typical embodiment, an aqueous sodium hydroxide solution is continuously added during the reaction period. In a preferred embodiment, the reaction is carried out at a temperature of about 65.degree. C. for a period of about eighteen hours, followed by gradually cooling the mixture to a room temperature of about 25.degree. C. over a period of about four hours. According to a method of the invention, the resulting reaction product is then filtered, re-suspended in methanol, filtered again, washed with a suitable aqueous solution (eg., two molar sodium chloride), and then washed with de-ionized water. According to an embodiment, the resultant solid product is then dried under suitable conditions, such as at a temperature of about 60.degree. C. in an air-drying oven. The dried solid can then be subsequently processed. In a preferred embodiment, the solid is ground and passed through an 80 mesh sieve.
 


Claim 1 of 2 Claims

1. A method for treating Syndrome X in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of colesevelam or a pharmaceutically acceptable salt thereof, alone or in combination with an antihyperlipidemic agent; a plasma HDL-raising agent; an antihypercholesterolemic agent; an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor; a cholesterol absorption inhibitor; a bile acid sequestrant anion exchange resin; an LDL (low density lipoprotein) receptor inducer; a fibrate; vitamin B.sub.6 (also known as pyridoxine) or a pharmaceutically acceptable salt thereof; vitamin B.sub.12; an anti-oxidant vitamin; an angiotensin II antagonist converting enzyeme inhibitor; or a platelet aggregation inhibitor.
 

 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]