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Title:  Use of rare earth compounds for the prevention of kidney stone disease
United States Patent: 
7,192,609
Issued: 
March 20, 2007

Inventors: 
Abrams; Michael J. (Custer, WA), Bridger; Gary J. (Bellingham, WA), Fricker; Simon P. (Langley, CA), Idzan; Stefan R. (Surrey, CA)
Assignee: 
Shire International Licensing B.V. (Amsterdam, NL)
Appl. No.: 
10/128,783
Filed: 
April 22, 2002


 

Pharm Bus Intell & Healthcare Studies


Abstract

Conditions such as kidney stones, which are characterized by undesired absorption of oxalate from the intestinal tract are conveniently treated using nontoxic salts of rare earth metal ions.

Description of the Invention

TECHNICAL FIELD

This invention relates to a method of preventing or treating urolithiasis (kidney stone disease) by administering rare earth salts, e.g., Lanthanum salts, to bind dietary oxalate and preventing its absorption into the gastrointestinal tract.

BACKGROUND OF THE INVENTION

Nephrolithiasis or urolithiasis is a common disorder defined as the development of stones within the urinary tract such as the kidney stone disease. This disorder represents a serious health problem. Depending on local conditions, between 1 and 14% of the population suffers from this condition. The economic impact of urolithiasis in the U.S. was estimated to be $1.83 billion in 1993 (Grases, et al., International Urology and Nephrology, 31(5) pp. 591 600 (1999)). Current preventative/treatment for urolithiasis are not easy to take and not that effective, e.g., potassium citrate tablets.

Calcium oxalate is the dominant component in kidney stones. The amount of oxalate excreted in urine has a significant impact on calcium oxalate supersaturation and kidney stone formation (R. Holmes, et al., Kidney International, 59, pp. 270 276 (2001)). In addition, calcium oxalate is also known to be associated with arthritis (Reginato A J, Kumik B R C: "Calcium oxalate and other crystals associated with kidney disease and arthritis," Semin Arthirtis Rheum 18:198, 1989).

PCT publication WO 99/22744 suggests the use of aliphatic polyamines to reduce the levels of oxalate in the digestive tract. This publication suggests that the polyamines be administered orally optionally in the presence of enzymes, such as oxalate decarboxylase or oxalate oxidase which can decompose oxalate. Various forms of oral dosage are described. The contents of this publication are incorporated herein by reference.

Hydrates of lanthanum carbonate [La.sub.2(CO.sub.3).sub.3] are described in U.S. Pat. No. 5,968,976 and WO 96/30029 for treating hyperphosphataemia in patients with renal failure by removing elevated levels of phosphates. This treatment is especially useful in patients undergoing kidney dialysis. These compounds are particularly preferred.

There exists a need for agents that bind oxalate and thereby inhibit or prevent stone formation in the kidneys. The present invention addresses this need by using rare earth compounds to lower levels of oxalate in animals, including humans.

Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents. Further, all documents referred to throughout this application are hereby incorporated in their entirety by reference herein.

DISCLOSURE OF THE INVENTION

The invention concerns methods to control, prevent, or treat subjects who are at risk for or who exhibit the symptomology of oxalate deposits in the kidneys--i.e., kidney stones, through the oral administration of rare earth salts, e.g. lanthanum salts, with high affinity oxalate binding properties.

Thus, in one aspect, the invention is directed to a method to inhibit the formation of kidney stones in a subject which method comprises administering to the gastrointestinal tract of said subject, an effective amount of a nontoxic rare earth salt, optionally in hydrated form. In typical embodiments, the rare earth salt is of the formula [RE].sub.a[X].sub.b.cH.sub.20 (1)

wherein RE represents a rare earth cation, X represents a nontoxic anion, a and b are of suitable relative values so that a neutral salt is formed, and c has a value of 0 10.

In another aspect, the invention is directed to a method to modulate the absorption of oxalate from the gastrointestinal tract of a subject which method comprises administering the compounds of formula (1) to a subject in need of such treatment.

In another aspect, the invention is directed to the use of an optionally hydrated rare earth nontoxic salt to prepare a medicament for the treatment of subjects at risk for or exhibiting symptoms of oxalate-based kidney stones.

MODES OF CARRYING OUT THE INVENTION

The invention provides pharmaceutical compositions using nontoxic salts of rare earth elements optionally in hydrated form. The rare earth cations are typically trivalent anions of the lanthanide series including, but not limited to, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Y and Sc, preferably La, Y and Ce. The cation is balanced by negatively charged counterions or mixtures of counterions selected from carbonate, chloride, formate, and acetate, preferably carbonate. The subscripts a and b in formula (1) above are dependent on the nature of the counterion and are selected so as to obtain a neutral salt. Waters of hydration may be present and, if present, may include as many as 10 waters of hydration, preferably less than eight, more preferably less than seven.

Preferred rare earth salts are those of yttrium, lanthanum and cerium. These rare earth salts can be counterbalanced by counterions such as acetates, chlorides or carbonates, with the carbonates being the most preferred. Also preferred are hydrated forms of these salts, especially hydrates with waters of hydration of less than 7 moles water per mole of salt, preferably 3 5 waters of hydration.

The compositions of the invention are designed for removal of oxalates from the gastrointestinal tract. Administration of these compositions is preferably to the upper digestive tract, most conveniently by oral administration. The compounds are effective over a pH range encountered in these locations which ranges from pH 2 in the stomach to pH 7 in regions downstream thereof. The compositions of the invention are not subject to degradation at high pH, and thus it is unnecessary to take special precautions, such as the supply of enteric coatings for oral administration.

The conditions characterized by kidney stones are believed to be related to inappropriate absorption of oxalate from the intestinal tract; inhibition of such absorption appears useful in controlling this condition. While not intending to be bound by any theory, applicants specifically include kidney stones among conditions that are affected by excessive oxalate absorption from the gastrointestinal tract. In addition, inappropriate absorption of oxalate from the gastrointestinal tract is itself a condition which requires remediation. The sequelae of such inappropriate absorption include the symptomology of kidney stones, but other deposits of oxalate may form in other organs as well or the levels of oxalate in the bloodstream may themselves be deleterious. Thus, any subject who exhibits levels of oxalate in the blood or serum that are higher than a normal level is also a candidate for treatment according to the method of the invention. Methods for determining oxalate levels in the diet and in the bloodstream or serum are known in the art.

Pharmaceutical compositions for oral administration according to the invention may be formulated and manufactured using methods well known in the art. Suitable diluents, carriers, excipients and other components are also well known. The compositions may be desirably be in a dosage form, to provide a single daily dose, or a number of sub-daily dosages. Conventional pharmacological methods may be used to ascertain suitable dose levels. Suitable formulations appropriate for any route of administration are known in the art and will be found, for example, in Remington's Pharmaceutical Sciences, latest ed., Mack Publishing Co., Easton, Pa. Suitable forms for oral administration include solid forms for oral administration include solid forms such as tablets, capsules and dragees and liquid forms such as suspensions or syrups. In addition to diluents and carriers, it is conventional in the formulation of oral preparations to include non-active ingredients such as thickeners, taste-improving components and coloring agents. The compound in the pharmaceutical composition may also be coated or treated to provide delayed-release forms. Preferably, the required daily dosage is given in tablet form, e.g., chewable tablet form.

By "treat" is meant either to ameliorate a condition that already exists or to inhibit the acquisition of a condition or further accretion of a condition that does not yet exist or that exists in a form that has a potential for progressing to more undesirable levels. Thus, by "treat" or "treatment" includes both therapeutic and prophylactic uses.

Individuals who may be treated by the methods of the invention include those who exhibit symptomology of kidney stones, have confirmed diagnosis of kidney stones, or are suspected by virtue of alternative symptoms of this condition. Also suitable subjects for the methods of the invention are those who would benefit from the removal of oxalate from the intestines generally; individuals with diets having high levels of oxalate intake, for example, would also be included. Further, individuals whose family history indicates a risk for inappropriate absorption of oxalate from the intestines would also be benefited. The treating practitioner would be in a position, based on tools of diagnosis available in the field, to identify those individuals who would benefit from modulation of the absorption of oxalate from the gastrointestinal tract.

The compositions to be administered may include additional active ingredients such as the aliphatic polyamines disclosed as described above in WO 99/22744 and any other medications compatible with the rare earth salts which may be intended for treatment of other conditions also experienced by the subject. While not intending to be bound by any theory, it is believed that the rare earth compounds of the invention form insoluble materials with the dietary oxalate and effect the excretion of the insolubilized oxalate from the subject without providing the opportunity of the oxalate to enter the urinary system.



Claim 1 of 10 Claims

1. A method of treating a condition characterized by unwanted absorption of oxalate from the gastrointestinal tract of a subject diagnosed as exhibiting said unwanted absorption which method comprises administering orally to said subject a hydrated lanthanum carbonate of the formula [La].sub.2[CO.sub.3].sub.3.cH.sub.2O, wherein c is 0 10, in an amount effective to inhibit the absorption of oxalate from the gastrointestinal tract, wherein the lanthanum carbonate is effective at binding oxalate in the presence of excess phosphate as the lanthanum carbonate passes through the stomach and the small intestine of the subject, the lanthanum carbonate preferentially binding the oxalate over the phosphate as the lanthanum carbonate passes through the small intestine.
 

 

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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.

 

 

     
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