Drug – bio-affecting and body treating compositions – Arteriosclerosis
Reexamination Certificate
1997-11-26
2002-07-23
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Arteriosclerosis
C424S078180, C424S078270
Reexamination Certificate
active
06423754
ABSTRACT:
BACKGROUND OF THE INVENTION
Reabsorption of bile acids-from the intestine conserves lipoprotein cholesterol in the bloodstream. Conversely, blood cholesterol levels can be diminished by reducing reabsorption of bile acids.
One method of reducing the amount of bile acids that are reabsorbed and, thus, reducing serum cholesterol is the oral administration of compounds that sequester the bile acids and cannot themselves be absorbed. The sequestered bile acids consequently are excreted.
Compounds which have been suggested for bile acid sequestration include various ion exchange polymers. One such polymer is cholestyramine, a copolymer of divinylbenzene/styrene and trimethylammonium methylstyrene. It has been long recognized that this polymer is unpalatable, gritty, and constipating. More recently, various polymers have been suggested which are characterized by hydrophobic substituents and quaternary ammonium radicals substituted upon an amine polymer backbone (Ahlers, et al. U.S. Pat. Nos. 5,428,112 and 5,430,110 and McTaggert, et al., U.S. Pat. 5,462,730, which are incorporated herein by reference).
Thus, there is still a need to discover superior bile acid sequestrants.
SUMMARY OF THE INVENTION
The invention relates to the unexpected discovery that a new class of ion exchange resins have improved bile salt sequestration properties resulting in reduced dosages, which improve patient tolerance and compliance, thereby improving the palatability of the composition and are relatively easy to manufacture. The polymers, employed in the invention comprise non-absorbable, and optionally cross-linked polyamines as defined herein. The properties of the polymer which gave rise to the present invention were discovered during clinical trials of the polymer for its use in binding phosphate in patients suffering from hyperphosphatemia. The polyamines of the invention are characterized by one or more monomeric units of the formula:
and salts thereof, where n is a positive integer and x is 0 or an integer between 1 and about 4. The polymer can be characterized by the substantial absence of one or more alkylated amine monomers and/or the substantial absence of one or more trialkylammonium alkyl groups. In preferred embodiments, the polymer is crosslinked by means of a multifunctional crosslinking agent.
The invention provides an effective treatment for removing bile salts from a patient (and thereby reducing the patient's cholesterol level), particularly in patients with a serum LDL level of at least about 130 mg/dL. The invention also provides for the use of the polymers described herein for the manufacture of a.medicament for the treatment of hypercholesterolemia or for bile acid sequestration.
Other features and advantages will be apparent from the following description of the preferred embodiments thereof and from the claims.
REFERENCES:
patent: 2874132 (1959-02-01), Riener
patent: 3288770 (1966-11-01), Butler
patent: 3308020 (1967-03-01), Wolf et al.
patent: 3383281 (1968-05-01), Wolf et al.
patent: 3562266 (1971-02-01), Minisci et al.
patent: 3692895 (1972-09-01), Nelson et al.
patent: 3780171 (1973-12-01), Irmscher et al.
patent: 3787474 (1974-01-01), Daniels et al.
patent: 3801641 (1974-04-01), Payot et al.
patent: 3803237 (1974-04-01), Lednicer et al.
patent: 3980770 (1976-09-01), Ingelman et al.
patent: 4027009 (1977-05-01), Grier et al.
patent: 4071478 (1978-01-01), Shen et al.
patent: 4098726 (1978-07-01), Wagner et al.
patent: 4101461 (1978-07-01), Strop et al.
patent: 4111859 (1978-09-01), Strop et al.
patent: 4205064 (1980-05-01), Wagner et al.
patent: 4217429 (1980-08-01), Wagner et al.
patent: 4340585 (1982-07-01), Borzatta et al.
patent: 4426489 (1984-01-01), Wessling et al.
patent: 4528347 (1985-07-01), Harada
patent: 4540760 (1985-09-01), Harada et al.
patent: 4557930 (1985-12-01), Kihara et al.
patent: 4559391 (1985-12-01), Ueda et al.
patent: 4605701 (1986-08-01), Harada et al.
patent: 4680360 (1987-07-01), Ueda et al.
patent: 4759923 (1988-07-01), Buntin et al.
patent: 5055197 (1991-10-01), Albright et al.
patent: 5189111 (1993-02-01), Danner
patent: 5236701 (1993-08-01), St. Pierre et al.
patent: 5374422 (1994-12-01), St. Pierre et al.
patent: 5414068 (1995-05-01), Bliem et al.
patent: 5428112 (1995-06-01), Ahlers et al.
patent: 5430110 (1995-07-01), Ahlers et al.
patent: 5451397 (1995-09-01), Albright et al.
patent: 5462730 (1995-10-01), McTaggart et al.
patent: 5487888 (1996-01-01), Mandeville et al.
patent: 5496545 (1996-03-01), Holmes-Farley et al.
patent: 5607669 (1997-03-01), Mandeville, III et al.
patent: 5624963 (1997-04-01), Mandeville, III et al.
patent: 0 081 291 (1983-06-01), None
patent: 0 162 388 (1985-11-01), None
patent: 0 373 852 (1990-06-01), None
patent: 0 432 995 (1991-06-01), None
patent: 0 459 632 (1991-12-01), None
patent: 798488 (1958-07-01), None
patent: 1 567 294 (1980-05-01), None
patent: 2 090 605 (1982-07-01), None
patent: 929391 (1993-06-01), None
patent: 6-32178 (1994-02-01), None
patent: WO91/18027 (1991-11-01), None
patent: WO92/10522 (1992-06-01), None
patent: WO94/04596 (1994-03-01), None
patent: WO94/27620 (1994-12-01), None
patent: WO95/34585 (1995-12-01), None
patent: WO 95/34585 (1995-12-01), None
patent: WO 95/34588 (1995-12-01), None
patent: WO96/39449 (1996-12-01), None
Chertow, G. M., et al., “Poly[allylamine Hydrochloride] (RenaGel): A Noncalcemic Phosphate Binder for the Treatment of Hyperphosphatemia in Chronic Renal Failure,”American Journal of Kidney Diseases, 29(1):66-71 (1997).
Burke, S.K., et al., “RenaGel®, a novel calcium-and aluminium-free phosphate binder, inhibits phosphate absorption in normal volunteers,”Nephrol Dial Transplant, 12:1640-1644 (1997).
Burke, S.K., et al., “RenaGel™, A Calcium and Aluminium Free Phosphate Binder, Inhibits Phosphate Absorption in Normal Volunteers,”Abstracts Bookfrom: XXXIII Congress of the European Renal Association European Dialysis and Transplant Associate, (Jun. 18, 1996).
Burke, S.K., et al., “RenaGel™, A Calcuim and Aluminium Free Phosphate Binder, Lowers Serum Phosphorus Hemodialysis Patients,”Abstracts Bookfrom: XXXIII Congress of the European Renal Association European Dialysis and Transplant Associate, (Jun. 18, 1996).
English Translation of Japanese Patent Laid-Open No. Hei 6-321786, Translated by Hosoda International Patent Office. (1994).
Kobayashi, Kazuo and Oka, Takayuki, “Polyamines for inhibition of intestinal absorption of bile acids,”Chemical Abstracts122(13) 27 Mar. 1995, Abstract No. 151392, XP002077304.
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).
Butler, G.B. and Do, C.H., “Comblike Cyclopolymers of Alkyldiallylamines and Alkyldiallylmethammonium Chlorides,” inWater-Soluble Polymers, eds. Shalaby, McCormick & Butler, Chapter 9, pp. 151-158 ACS Symposium Series 467 (1991).
Dubin, P.L. and Davis, D.D., “Quasi-Elastic Light Scattering of Polyelectrolyte-Micelle Complexes,”Macromolecules 17: 1294-1296 (1984).
Wang, G.-J. and Engberts, J., “Fluorescence probing of the formation of hydrophobic microdomains by cross-linked poly(alkylmethyldiallylammonium bromides) in aqueous solution,”Recl. Trav. Chim. Pays-Bas 113, 390-393 (1994).
Kunitake, T., et al., “Catalyses of Polymer Complexes. 4. Polysoap-Catalyzed Decarboxylation of 6-Nitrobenzisoxazole-3-carboxylate Anion. Importance of the Hydrophobic Environment in Activation of the Anion,”J. Org. Chem 42(2): 306-312 (1977).
Wang, G.-J. and Engberts, J., “Study of the Conformational State of Non-Cross-Linked and Cross-Linked Poly(alkylmethyldiallylammonium Chlorides) in Aqueous Solution by Fluorescence Probing,”Gazzetta Chimica Italiana, 125: 393-397 (1995).
Kuron, G.W., et al., “the Bile Acid Binding and Hypocholesterolemic Action of Two-Water-Soluble Polymers,”Atherosclerosis, 37 353-360 (1980).
Harada, S. and Arai, K., “The Cyclo-copolymerization of Dial
Burke Steven K.
Goldberg Dennis I.
Holmes-Farley Stephen Randall
Mandeville, III W. Harry
GelTex Pharmaceuticals Inc.
Hamilton Brook Smith & Reynolds P.C.
Webman Edward J.
LandOfFree
Method for treating hypercholesterolemia with polyallylamine... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for treating hypercholesterolemia with polyallylamine..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for treating hypercholesterolemia with polyallylamine... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2906558