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)
International Licensing B.V. (Amsterdam, NL)
Appl. No.: 10/128,783
Filed: April 22, 2002
Pharm Bus Intell
& Healthcare Studies
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
Description of the Invention
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
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
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
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
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
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
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