Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Polymer from ethylenic monomers only
Reexamination Certificate
1997-11-05
2004-04-27
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Polymer from ethylenic monomers only
C424S078120, C424S078180
Reexamination Certificate
active
06726905
ABSTRACT:
BACKGROUND OF THE INVENTION
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 Ca
3
(PO
4
)
2
, CaHPO
4
, or Ca(H
2
PO
4
)
2
. A variety of calcium salts, including calcium carbonate, calcium acetate (such as PhosLo® 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® 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® 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.
SUMMARY OF THE INVENTION
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.
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 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 “therapeutically effective amount” 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 R
1
and R
2
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, R
2
is methyl.
In another embodiment, the polymer to be administered is characterized by a repeat unit of Formula III or Formula IV wherein R
1
, R
2
and the nitrogen atom together form a cyclic structure, such as a saturated or unsaturated ring system. For example, R
1
and R
2
can together form a substituted or unsubstituted C
1
-C
12
-alkylene group, such as —(CH
2
)
n
— wherein n is from 2 to 12.
In Formulas III and IV, X
−
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,
Holmes-Farley Stephen Randall
Mandeville, III W. Harry
Genzyme Corporation
Hamilton Brook Smith & Reynolds P.C.
Webman Edward J.
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