Hyperphosphatemia frequently accompanies diseases associated with inadequate renal function, hypoparathyroidism, and certain other medical conditions. Hyperphosphatemia is typically defined as a serum phosphate level of greater than about 6 mg/dL. The condition, especially if present over extended periods of time, leads to severe abnormalities in calcium and phosphorus metabolism and can be manifested by aberrant calcification in joints, lungs, and eyes.
Therapeutic efforts to reduce serum phosphate levels include dialysis, reduction in dietary phosphate, and oral administration of insoluble phosphate binders to reduce gastrointestinal adsorption. Dialysis and reduced dietary phosphate are generally unable to adequately reverse hyperphosphatemia. Further disadvantages of these therapeutic regimens include the invasive nature of dialysis and difficulties associated with modifying dietary habits.
Therapy based upon oral administration of certain phosphate binders has also been suggested. Phosphate binders include calcium or aluminum salts. Calcium salts have been widely used to bind intestinal phosphate and prevent adsorption. The ingested calcium combines with phosphate to form insoluble calcium phosphate salts, such as Ca3(PO4)2, CaHPO4, or Ca(H2PO4)2. A variety of calcium salts, including calcium carbonate, calcium acetate (such as PhosLo(copyright) calcium acetate tablets), calcium citrate, calcium alginate and calcium ketoacid salts have been utilized for in vivo phosphate binding. The use of calcium salts, however, can result in hypercalcemia due to absorption of high amounts of ingested calcium. Hypercalcemia has been implicated in many serious side effects, such as cardiad arrhythmias, renal failure, and skin and visceral calcification. Frequent monitoring of serum calcium levels is required during therapy with calcium-based phosphate binders.
Aluminum-based phosphate binders, such as Amphojel(copyright) aluminum hydroxide gel, have also been used for treating hyperphosphatemia. These compounds complex with intestinal phosphate to form highly insoluble aluminum phosphate; the bound phosphate is unavailable for absorption by the patient. Prolonged use of aluminum gels leads to accumulations of aluminum, and often to aluminum toxicity, accompanied by such symptoms as encephalopathy, osteomalacia, and myopathy.
Selected ion exchange resins have also been suggested for use in binding phosphate. Those tested include Dowex(copyright) anion-exchange resins in the chloride form, such as XF 43311, XY 40013, XF 43254, XY 40011, and XY 40012 (Burt et al., J. Pharmaceutical Sci. 76: 379-383 (1987)). These. resins have several drawbacks for treatment of hyperphosphatemia, including poor binding efficiency, necessitating high doses for significant reduction of absorbed phosphate.
Thus, a need exists for improved phosphate binders which can be administered orally in acceptable dosage levels without resulting in many of the serious side effects discussed above.
The present invention relates to a method for lowering the serum phosphate level of a patient. The method comprises the step of administering to the patient a therapeutically effective amount of a polymer characterized by a diallylamine monomer or repeat unit. The amino nitrogen atom of the diallylamine repeat unit can be substituted by one or two substituents independently selected from among substituted and unsubstituted, normal, branched and cyclic alkyl groups, and aryl groups. When the diallylamine repeat unit comprises an ammonium or quaternary ammonium group, the monomer 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 a diallyamine monomer and at least one additional monomer. The additional monomer can be a second diallylamine monomer or a monomer which is not a diallylamine, such as substituted or unsubstituted acrylamide or sulfur dioxide.
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 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 relates to Applicant""s discovery that poly(diallylamine) polymers exhibit excellent phosphate-binding activity. The invention provides a method for lowering the serum phosphate level of a patient comprising administering to the patient a therapeutically effective amount of a polymer characterized by a diallylamine or N-substituted diallylamine monomer, or repeat unit.
As used herein, the term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount which is sufficient to decrease the serum phosphate level of the patient by a clinically significant amount. The patient can be an animal, for example, a mammal, or a human.
In one embodiment, the polymer to be administered is a poly(diallylamine) polymer. The polymer can be a homopolymer, wherein each of the diallylamine repeat units has the same nitrogen substituents, or a copolymer, for example, comprising two or more diallylamine repeat units having different amino nitrogen substituents. The polymer to be administered can also be a copolymer comprising one or more diallylamine repeat units and at least one additional repeat unit which is not a diallylamine. In these polymers, the diallylamine nitrogen atom can be unsubstituted or substituted with one or two substituents selected from among substituted and unsubstituted normal, branched and cyclic alkyl groups and substituted and unsubstituted aryl groups.
In one embodiment, the polymer to be administered is characterized by an amine-bearing monomeric unit of Formula 
or a combination thereof, wherein R is 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 halogen atoms, such as fluorine, chlorine, bromine and iodine atoms; alkyl; hydroxy; primary, secondary and tertiary amino; quaternary ammonium; alkoxy; carboxamido; sulfonamido; aryl; hydrazido; guanadyl; and ureyl. In a preferred embodiment, R is a methyl group.
In another embodiment, the polymer to be administered is characterized by a repeat unit of Formula III or of Formula IV, 
or a combination thereof, wherein R1 and R2 are each, independently, hydrogen; substituted or unsubstituted linear, branched or cyclic alkyl; or substituted or unsubstituted aryl. Suitable alkyl and aryl substituents include halogen atoms, such as fluorine, chlorine, bromine and iodine atoms; hydroxy; primary, secondary and tertiary amino; quaternary ammonium; alkoxy; carboxamido; sulfonamido; aryl; hydrazido; guanadyl; and ureyl. In a preferred embodiment, R2 is methyl.
In another embodiment, the polymer to be administered is characterized by a repeat unit of Formula III or Formula IV wherein R1, R2 and the nitrogen atom together form a cyclic structure, such as a saturated or unsaturated ring system. For example, R1 and R2 can together form a substituted or unsubstituted C1-C12-alkylene group, such as xe2x80x94(CH2)nxe2x80x94 wherein n is from 2 to 12.
In Formulas III and IV, Xxe2x88x92 is an anion, such as the conjugate base of a pharmaceutically acceptable acid. Such anions include chloride, citrate, tartrate, lactate, 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, Xxe2x88x92 is chloride.
In one embodiment, the polymer to be administered is characterized by a diallylamine repeat unit is of Formula I, Formula II, Formula III, or Formula IV, wherein the amino nitrogen atom is substituted with an ammonioalkyl substituent. Suitable ammonioalkyl substituents are of the general formula 
wherein R4, R5 and R6 are each, independently, a hydrogen atom or a C1-C24 alkyl group; n is an integer from 2 to about 20, preferably from 3 to about 6; and Xxe2x88x92 is an anion, such as a conjugate base of a pharmaceutically acceptable acid. Suitable examples of ammonioalkyl groups include, but are not limited to,
4-(dioctylmethylammonio)butyl;
3-(dodecyldimethylammonio)propyl;
3-(octyldimethylammonio)propyl;
3-(dodecyldimethylammonio)propyl;
5-(dodecyldimethylammonio)pentyl;
3-cylohexyldimetahylammonio)propyl;
3-(decyldimethylammonio)-2-hydroxypropyl;
3-(tridecylammonio)propyl;
3-(docosyldimethylammonio)propyl;
4-(dodecyldimethylammonio)butyl;
3-(octadecyldimethylammonio)propyl;
3-(hexyldimethylammonio)propyl;
3-(methyldioctylammonio)propyl;
3-(didecylmethylammonio)propyl;
3-(heptyrldimethylammonio)propyl;
3-(dimethylnonylammonio)propyl;
6-(dimethylundecylammonio)hexyl;
4-(heptyldimethylammonio)butyl;
3-(dimethylundecylammonio)propyl; and
3-(tetradecyldimethylammonio)propyl.
The polymer to be administered can be a copolymer comprising a diallylamine repeat unit, such as a repeat unit of Formula I, II, III, or IV, and at least one additional monomer. In one embodiment, the polymer is a copolymer comprising at least one monomer which is not a diallylamine. Suitable examples of such monomers include substituted and unsubstituted acrylate, acrylamide, methacrylate, methacrylamide, allylamine, triallylamine, tetrallylammonium ion, allyl alcohol, vinyl amine, vinyl alcohol, sulfur dioxide, and carbon dioxide. For example, the additional monomer can be a hydrophilic monomer, such as N-(2-hydroxyethyl)acrylamide or (3-hydroxypropyl)acrylate. Also included are the multifunctional crosslinking co-monomers which are discussed in detail below. Copolymers comprising a repeat unit which is not a diallylamine can have a wide range of compositions. Typically, the diallylamine monomer will constitute from about 10% to about 90% of the repeat units within the polymer.
The polymers of use in the present method can be linear or crosslinked. The polymer can be crosslinked, for example, by the incorporation within the polymer of a multifunctional comonomer. Suitable multifunctional co-monomers include diacrylates, triacrylates and. tetraacrylates, dimethacrylates, diacrylamides, diallylacrylamide, di(methacrylamides), triallylamine and tetraalylammonium ion. Specific examples include ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis(methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide) ethylidene bis(methacrylamide), pentaerythritol tetraacrylate, trimethylolpropane triacrylate, bisphenol A dimethacrylate, and bisphenol A diacrylate. Other suitable multifunctional monomers include polyvinylarenes, such as divinylbenzene. The amount of crosslinking agent is typically between about 1.0% and about 30% by weight relative to the weight of the polymer, preferably from about 5% to about 25% by weight.
The polymer can also be crosslinked by bridging units which link amino groups on adjacent polymer strands. Suitable bridging units include straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups. Examples of suitable bridging units include xe2x80x94(CH2)nxe2x80x94, wherein n is an integer from about 2 to about 20; xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94; xe2x80x94C(O)CH2CH2C(O)xe2x80x94; xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94Oxe2x80x94(CH2)mxe2x80x94Oxe2x80x94CH(OH)xe2x80x94CH2xe2x80x94, wherein m is an integer from about 2 to about 4; xe2x80x94C(O)xe2x80x94(C6H2(COOH)2)xe2x80x94C(O)xe2x80x94 and xe2x80x94C(O)NH(CH2)pNHC(O)xe2x80x94, wherein p is an integer from about 2 to about 20.
Advantageously, crosslinking the polymers renders the polymers non-adsorbable and stable in the patient. A xe2x80x9cstablexe2x80x9d polymer composition, when administered in therapeutically effective amounts, does not dissolve or otherwise decompose to form potentially harmful byproducts, and remains substantially intact.
Polymers of use in the present method are, preferably, of a molecular weight which enables them to reach and remain in the gastrointestinal tract for a sufficient period of time to bind a significant amount of phosphate. The polymers should, thus, be of sufficiently high molecular weight to resist, partially or completely, absorption from the gastrointestinal tract into other regions of the body. The resulting polymer/phosphate complex should then be excreted from the body. Suitable linear or branched (non-crosslinked) polymers have molecular weights which range from about 2,000 Daltons to about 500,000 Daltons, preferably from about 5,000 Daltons to about 150,000 Daltons. Crosslinked polymers, however, are not generally characterized by molecular weight. The crosslinked polymers discussed herein should be sufficiently crosslinked to-resist adsorption from the gastrointestinal tract.
The polymer network can be administered orally to a patient in a dosage of about 1 mg/kg/day to about 10 g/kg/day; the particular dosage will depend on the individual patient (e.g., the patient""s weight and the extent of phosphate removal required). The polymer can be administered either in hydrated or dehydrated form, and can be flavored or added to a food or drink, if desired, to enhance patient acceptance. Additional ingredients such as other phosphate binders (including other polymers, calcium salts, and aluminum salts) or inert ingredients, such as artificial coloring agents, may be added as well.
Examples of suitable forms for administration include pills, tablets, capsules, and powders (i.e. for sprinkling on food). The pill, tablet, capsule or powder can be coated with a substance capable of protecting the composition from the gastric acid in the patient""s stomach for a period of time sufficient for the composition to pass undisintegrated into the patient""s small intestine. The polymer can be administered alone, 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 may 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 carriers, 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.
The polymeric phosphate binder can be co-administered to the patient with a calcium supplement. The calcium supplement is, preferably, administered orally in an amount which is effective to increase the physiological calcium concentration of the patient. The calcium supplement can be administered prior to, simultaneous with, or subsequent to administration of the polymeric phosphate binder. The calcium supplement can be any pharmaceutically acceptable calcium salt, such as calcium acetate, calcium carbonate, calcium gluconate, calcium lactate, calcium levinulate, calcium citrate, calcium lactobionate and calcium chloride. Preferably, the calcium supplement to be administered serves as both a calcium source and a buffering agent, such as calcium carbonate or calcium acetate.
The polymeric phosphate binder and the calcium supplement can be administered individually or as components of a single composition. For example, the calcium supplement can be included in one of the polymeric phosphate binder formulations discussed above. In this case, the calcium supplement can additionally serve as a carrier or diluent for the polymeric phosphate binder. For example, the calcium supplement, such as calcium carbonate, can serve as a hardening agent in a tablet form of the polymeric phosphate binder composition. Such a composition provides the polymeric phosphate binder, a calcium supplement and a carbonate supplement in a single dosage form.
Polymers of use in the present method can be prepared using techniques known in the art of polymer synthesis (see for example, Shalaby et al., ed., Water-Soluble Polymers, American Chemical Society, Washington D.C. (1991)). For example, the appropriate monomer can be polymerized by methods known in the art, for example, via a free radical addition process. In this case the polymerization mixture includes a free-radical initiator, such as a free radical initiator selected from among those which are well known in the art of polymer chemistry. Suitable free-radical initiators include azobis(isobutyronitrile), azobis(4-cyanovaleric acid), azobis(amidinopropane) dihydrochloride, potassium persulfate, ammonium persulfate and potassium hydrogen persulfate. The free radical initiator is preferably present in the reaction mixture in an amount ranging from about 0.1 mole percent to about 5 mole percent relative to the monomer.
The polymer can be crosslinked, for example, by including a multifunctional co-monomer as the crosslinking agent in the reaction mixture. A multifunctional co-monomer can be incorporated into two or more growing polymer chains, thereby crosslinking the chains. Suitable multifunctional co-monomers include those discussed above. The amount of crbsslinking agent added to the reaction mixture is, generally, between 1.0% and 3b% by weight relative to the combined weight of the polymer and the crosslinking agent, and preferably from about 2.5% to about 25% by weight.
The multifunctional co-monomer can also take the form of a multifunctional diallylamine, such as a bis(diallylamino)alkane or a bis(diallylalkylammonio)alkane. Suitable monomers of this type include 1,10-bis(diallylmethylammonio)decane dibromide and 1,6-bis(diallylmethylammonio)hexane dibromide, each of which can be formed by the reaction of diallylmethylamine with the appropriate dibromoalkane.
The polymers to be administered can also be crosslinked subsequent to polymerization by reacting the polymer with one or more crosslinking agents having two or more functional groups, such as electrophilic groups, which react with amine groups to form a covalent bond. Crosslinking in this case can occur, for example, via nucleophilic attack of the polymer amino groups on the electrophilic groups. This results in the formation of a bridging unit which links two or more amino nitrogen atoms from different polymer strands. Suitable crosslinking agents of this type include compounds having two or more groups selected from among epoxide, acyl-X and alkyl-X, wherein X- is a suitable leaving group, such as a halide, acylate, tosylate or mesylate group. Examples of such compounds include epichlorohydrin, succinyl dichloride, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, pyromellitic dianhydride and dihaloalkanes. The crosslinking agent can also be an xcex1,xcfx89-alkylene diisocyanate, for example OCN(CH2)pNCO, wherein p is an integer from about 2 to about 20. The polymer can be reacted with an amount of crosslinking agent equal to from about 0.5 to 40 mole percent relative to the amino groups within the polymer, depending upon the extent of crosslinking desired.
A polymer comprising alkylated amino groups can be formed by reacting a preformed polymer with a suitable alkylating agent, or by polymerizing an alkylated monomer. Suitable alkylated monomers can be prepared by reacting diallylamine or a diallylamine derivative, such as diallylmethylamine, with an alkylating agent. As used herein, the term xe2x80x9calkylating agentxe2x80x9d refers to a compound which reacts with an amino group to form a nitrogen-carbon bond thereby adding an alkyl or alkyl derivative substituent to the nitrogen atom. Suitable alkylating agents are compounds comprising an alkyl group or alkyl derivative which is bonded to a leaving group, such as a halo, tosylate, mesylate or epoxy group. Examples of preferred alkylating agents include C1-C24-alkyl halides, for example, n-butyl halides, n-hexyl halides, n-decyl halides, and n-octadecyl halides; C2-C24-dihaloalkanes, for example, 1,10-dihalodecanes; C1-C24-hydroxyalkyl halides, for example, 11-halo-1-undecanols; C1-C24-arylalkyl halides, for example, benzyl halide; C2-C24-alkylepoxy ammonium salts, for example, glycidylpropyl-trimethylammonium salts; and C2-C24-epoxyalkylamides, for example, N-(2,3-epoxypropyl)butyramide or N-(2,3-epoxypropyl)hexanamide. Preferred alkylating agents include halodecane, and halododecane, where in each case xe2x80x9chaloxe2x80x9d represents a chloro, bromo or iodo substituent.
Diallylamine polymers-having amino groups which bear quaternary ammonium-substituted alkyl groups can be prepared using alkylating agents such as (X-alkyl)ammonium salts, wherein X represents a suitable leaving group, as described above. These compounds can be prepared by the reaction of an appropriate dihaloalkane, such as a bromochloroalkane, with a tertiary amine. Suitable alkylating agents of this type 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)docbsyldimethylammbnium 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-bromopropyl)heptyldimethylammonium bromide;
(3-bromopropyl)dimethylnonylammonium bromide;
(6-bromohexyl)dimethylundecylammonium bromide;
(4-chlorobutyl)heptyldimethylammonium bromide;
(3-chloropropyl)dimethylundecylammonium bromide; and
(3-chloropropyl)tetradecyldimethylammonium bromide.
Each of the alkylating agents described above can also exist and be used as a salt in combination with an anion other than bromide. For example, these and similar alkylating agents can be prepared and used as salts with a wide range of anions, including chloride, iodide, acetate, p-toluenesulfonate and methanesulfonate.
The invention will now be further and specifically described by the following examples.