U.S. patent application number 15/893861 was filed with the patent office on 2018-06-14 for phosphate-binding magnesium salts and uses thereof.
The applicant listed for this patent is Cypress Pharmaceuticals, Inc.. Invention is credited to Charles E. Day, Robert L. Lewis.
Application Number | 20180161365 15/893861 |
Document ID | / |
Family ID | 41215240 |
Filed Date | 2018-06-14 |
United States Patent
Application |
20180161365 |
Kind Code |
A1 |
Lewis; Robert L. ; et
al. |
June 14, 2018 |
Phosphate-Binding Magnesium Salts And Uses Thereof
Abstract
The present invention provides, among other things, compositions
and methods suitable for the treatment of hyperphosphatemia based
on phosphate-binding magnesium salts. In some embodiments, the
present invention provides compositions and methods suitable for
the treatment of hyperphosphatemia based on the combination of
phosphate-binding magnesium and calcium salts.
Inventors: |
Lewis; Robert L.; (Madison,
MS) ; Day; Charles E.; (Leitchfield, KY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cypress Pharmaceuticals, Inc. |
Morristown |
NJ |
US |
|
|
Family ID: |
41215240 |
Appl. No.: |
15/893861 |
Filed: |
February 12, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15477325 |
Apr 3, 2017 |
9889157 |
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15893861 |
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15155366 |
May 16, 2016 |
9610267 |
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15477325 |
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13856084 |
Apr 3, 2013 |
9339481 |
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15155366 |
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13544949 |
Jul 9, 2012 |
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13856084 |
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12422012 |
Apr 10, 2009 |
8247000 |
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13544949 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/191 20130101;
A61K 9/2806 20130101; A61K 33/08 20130101; A61P 3/00 20180101; A61K
9/4891 20130101; A61P 39/04 20180101; A61K 33/06 20130101; A61K
31/19 20130101; A61K 9/28 20130101; A61P 7/00 20180101; A61K 31/197
20130101; A61K 33/10 20130101; A61K 31/715 20130101; A61K 9/0053
20130101 |
International
Class: |
A61K 33/06 20060101
A61K033/06; A61K 9/48 20060101 A61K009/48; A61K 9/28 20060101
A61K009/28; A61K 9/00 20060101 A61K009/00 |
Claims
1-106. (canceled)
107. A therapeutic composition comprising magnesium glycinate,
wherein the composition comprises about 20 mg to about 1200 mg
magnesium, the composition is formulated for oral administration
and the composition comprises an enteric coating.
108. The composition of claim 107, wherein the composition
comprises about 20 mg to about 600 mg magnesium.
109. The composition of claim 107, wherein the enteric coating
comprises one or more of acetyltributyl citrate, carbomers,
cellulose acetate phthalate, cellulose acetate succinate, ethyl
cellulose, guar gum, hypromellose acetate succinate, hypromellose
phthalate, polymethacrylates, polyvinyl acetate phthalate, shellac,
tributyl citrate, triethyl citrate, white wax or zein.
110. The composition of claim 107, further comprising at least one
calcium salt.
111. The composition of claim 110, wherein the at least one calcium
salt is selected from the group consisting of calcium acetate,
calcium aceturate, calcium adipate, calcium alaninate, calcium
alginate, calcium aminobutyrate, calcium arginate, calcium
ascorbate, calcium aspartate, calcium benzoate, calcium besylate,
calcium betainate, calcium bromide, calcium buteprate, calcium
butyrate, calcium caproate, calcium carbesilate, calcium carbonate,
calcium carboxymethylcellulose, calcium camitinate, calcium
chloride, calcium ciclotate, calcium citrate, calcium cypionate,
calcium enanthate, calcium esylate, calcium ethandisulfonate,
calcium formate, calcium fumarate, calcium glucarate, calcium
gluceptate, calcium gluconate, calcium glucuronate, calcium
glutamate, calcium glycinate, calcium hippurate, calcium hyclate,
calcium hydroxide, calcium iodide, calcium isethionate, calcium
lactate, calcium lactobionate, calcium levulinate, calcium
lysinate, calcium malate, calcium maleate, calcium mesylate,
calcium metilsulfate, calcium methylsulfate, calcium naphthoate,
calcium napsylate, calcium nicotinate, calcium nitrate, calcium
oleate, calcium orotate, calcium oxide, calcium oxoglurate, calcium
pamoate, calcium pantothenate, calcium picolinate, calcium
pivalate, calcium polygalacturonate, calcium propionate, calcium
sorbate, calcium steaglate, calcium stearate, calcium
stearyl-2-lactylate, calcium succinate, calcium sulfate, calcium
sulfite, calcium tartrate, calcium tebutate, calcium tosylate,
calcium triflutate, calcium xinafoate, and combination thereof.
112. The composition of claim 110, wherein the mass ratio of the at
least one calcium salt to magnesium glycinate is between about
100:1 and about 1:100.
113. The composition of claim 110, wherein the mass ratio of the at
least one calcium salt to magnesium glycinate is between about 5:4
and about 4:5.
114. The composition of claim 110, wherein the mass ratio of the at
least one calcium salt to magnesium glycinate is about 1:1.
115. The composition of claim 110, wherein the at least one calcium
salt comprises calcium acetate.
116. The composition of claim 110, wherein the composition is in a
form of a tablet, a cachet, a hard gelatin capsule, a soft gelatin
capsule, a lozenge, suspension, or a bead.
117. A method of treating hyperphosphatemia comprising
administering the composition of claim 107 to a subject in need
thereof.
118. The method of claim 117, wherein the composition comprises
about 20 mg to about 600 mg magnesium.
119. The method of claim 117, wherein the enteric coating comprises
one or more of acetyltributyl citrate, carbomers, cellulose acetate
phthalate, cellulose acetate succinate, ethyl cellulose, guar gum,
hypromellose acetate succinate, hypromellose phthalate,
polymethacrylates, polyvinyl acetate phthalate, shellac, tributyl
citrate, triethyl citrate, white wax or zein.
120. The method of claim 117, wherein the composition further
comprises at least one calcium salt.
121. The method of claim 120, wherein the at least one calcium salt
is selected from the group consisting of calcium acetate, calcium
aceturate, calcium adipate, calcium alaninate, calcium alginate,
calcium aminobutyrate, calcium arginate, calcium ascorbate, calcium
aspartate, calcium benzoate, calcium besylate, calcium betainate,
calcium bromide, calcium buteprate, calcium butyrate, calcium
caproate, calcium carbesilate, calcium carbonate, calcium
carboxymethylcellulose, calcium camitinate, calcium chloride,
calcium ciclotate, calcium citrate, calcium cypionate, calcium
enanthate, calcium esylate, calcium ethandisulfonate, calcium
formate, calcium fumarate, calcium glucarate, calcium gluceptate,
calcium gluconate, calcium glucuronate, calcium glutamate, calcium
glycinate, calcium hippurate, calcium hyclate, calcium hydroxide,
calcium iodide, calcium isethionate, calcium lactate, calcium
lactobionate, calcium levulinate, calcium lysinate, calcium malate,
calcium maleate, calcium mesylate, calcium metilsulfate, calcium
methylsulfate, calcium naphthoate, calcium napsylate, calcium
nicotinate, calcium nitrate, calcium oleate, calcium orotate,
calcium oxide, calcium oxoglurate, calcium pamoate, calcium
pantothenate, calcium picolinate, calcium pivalate, calcium
polygalacturonate, calcium propionate, calcium sorbate, calcium
steaglate, calcium stearate, calcium stearyl-2-lactylate, calcium
succinate, calcium sulfate, calcium sulfite, calcium tartrate,
calcium tebutate, calcium tosylate, calcium triflutate, calcium
xinafoate, and combination thereof.
122. The method of claim 120, wherein the mass ratio of the at
least one calcium salt to magnesium glycinate is between about
100:1 and about 1:100.
123. The method of claim 120, wherein the mass ratio of the at
least one calcium salt to magnesium glycinate is between about 5:4
and about 4:5.
124. The method of claim 120, wherein the mass ratio of the at
least one calcium salt to magnesium glycinate is about 1:1.
125. The method of claim 120, wherein the at least one calcium salt
comprises calcium acetate.
126. The method of claim 120, wherein the composition is in a form
of a tablet, a cachet, a hard gelatin capsule, a soft gelatin
capsule, a lozenge, suspension, or a bead.
Description
BACKGROUND OF THE INVENTION
[0001] Like other diseases for which there is no cure, chronic
kidney disease takes an ever-increasing toll on patients who have
it. As the disease progresses, the kidney becomes less efficient at
removing various ions from the blood. Among these ions is
phosphate, which can form insoluble particles when combined with
calcium. In end-stage renal disease, the final stage of chronic
kidney disease, kidney function is so compromised that phosphate
levels in the blood (serum) become markedly elevated. This
condition, known as hyperphosphatemia, carries with it many grave
health risks. For example, when serum phosphate and calcium levels
are above a certain threshold, hardened deposits may form
throughout the body, endangering circulation. It is therefore very
important to control serum phosphate levels in patients with
end-stage renal disease.
[0002] Patients with end-stage renal disease may be advised to eat
a diet low in phosphate. However, phosphate is present at some
level in almost all the foods we eat. For this reason, phosphate
binders were developed. Phosphate binders are compounds taken
orally and which act in the gastrointestinal tract to bind
phosphate and keep it from being absorbed. Phosphate binders are
generally taken with each meal. Phosphate binders known in the art
include, for example, various salts of aluminum and calcium, as
well as some chemically synthesized crosslinked polymers. There are
clinical circumstances in which the administration of aluminum or
calcium salts is ill-advised. In animal models, certain crosslinked
polymers carry with them elevated risks of carcinogenesis.
Therefore, there is a need for safer and more effective phosphate
binders.
SUMMARY OF THE INVENTION
[0003] The present invention encompasses the discovery that certain
magnesium salts are surprisingly effective in phosphate binding.
Thus, the present invention provides therapeutic compositions and
methods for removing phosphate from a mammalian subject based on
one or more phosphate-binding magnesium salts. Among other things,
phosphate-binding magnesium salts of the invention are particularly
useful when they are used in combination with other
phosphate-binders (e.g., calcium salts) in treating
hyperphosphatemia. For example, a combination of a magnesium salt
with a calcium salt may provide effective phosphate-binding while
reducing the total dose of calcium and, at the same time, providing
better nutritional balance. Therefore, the present invention
provides phosphate-binding compositions and methods that are safer
and more effective.
[0004] In one aspect, the present invention provides a composition
suitable for treating hyperphosphatemia comprising a
therapeutically effective dose of at least one calcium salt and at
least one phosphate-binding magnesium salt. In some embodiments,
the at least one phosphate-binding magnesium salt binds at least
about 50 mg phosphate per gram magnesium salt.
[0005] In some embodiments, the therapeutically effective dose of
at least one calcium salt contains about 20 mg to 1200 mg of
calcium. In some embodiments, the therapeutically effective dose of
at least one calcium salt contains less than about 2000 mg (e.g.,
less than about 1800 mg, less than about 1600 mg, less than about
1400 mg, less than about 1200 mg, less than about 1000 mg, less
than about 800 mg, less than about 600 mg, less than about 400 mg,
less than about 200) of calcium.
[0006] In some embodiments, the therapeutically effective dose of
at least one phosphate-binding magnesium salt contains about 20 mg
to 1200 mg magnesium. In some embodiments, the therapeutically
effective dose of at least one phosphate-binding magnesium salt
comprises less than about 1200 mg magnesium.
[0007] In some embodiments, the at least one calcium salt is
selected from the group consisting of calcium acetate, calcium
aceturate, calcium adipate, calcium alaninate, calcium alginate,
calcium aminobutyrate, calcium arginate, calcium ascorbate, calcium
aspartate, calcium benzoate, calcium besylate, calcium betainate,
calcium bromide, calcium buteprate, calcium butyrate, calcium
caproate, calcium carbesilate, calcium carbonate, calcium
carboxymethylcellulose, calcium carnitinate, calcium chloride,
calcium ciclotate, calcium citrate, calcium cypionate, calcium
enanthate, calcium esylate, calcium ethandisulfonate, calcium
formate, calcium fumarate, calcium glucarate, calcium gluceptate,
calcium gluconate, calcium glucuronate, calcium glutamate, calcium
glycinate, calcium hippurate, calcium hyclate, calcium hydroxide,
calcium iodide, calcium isethionate, calcium lactate, calcium
lactobionate, calcium levulinate, calcium lysinate, calcium malate,
calcium maleate, calcium mesylate, calcium metilsulfate, calcium
methylsulfate, calcium naphthoate, calcium napsylate, calcium
nicotinate, calcium nitrate, calcium oleate, calcium orotate,
calcium oxide, calcium oxoglurate, calcium pamoate, calcium
pantothenate, calcium picolinate, calcium pivalate, calcium
polygalacturonate, calcium propionate, calcium sorbate, calcium
steaglate, calcium stearate, calcium stearyl-2-lactylate, calcium
succinate, calcium sulfate, calcium sulfite, calcium tartrate,
calcium tebutate, calcium tosylate, calcium triflutate, calcium
xinafoate, and combination thereof.
[0008] In some embodiments, the at least one phosphate-binding
magnesium salt selected from the group consisting of magnesium
aminobutyrate, magnesium arginate, magnesium aspartate, magnesium
betainate, magnesium carnitinate, magnesium glycinate, magnesium
hydroxide, magnesium lysinate, magnesium oxide, magnesium
propionate, and combination thereof.
[0009] In some embodiments, the mass ratio of the at least one
calcium salt to the at least one phosphate-binding magnesium salt
is between about 100:1 and about 1:100. In some embodiments, the
mass ratio of the at least one calcium salt to the at least one
phosphate-binding magnesium salt is between about 10:1 and about
1:10. In some embodiments, the mass ratio of the at least one
calcium salt to the at least one phosphate-binding magnesium salt
is between about 3:1 and about 1:3. In some embodiments, the mass
ratio of the at least one calcium salt to the at least one
phosphate-binding magnesium salt is between about 2:1 and about
1:2. In some embodiments, the mass ratio of the at least one
calcium salt to the at least one phosphate-binding magnesium salt
is between about 3:2 and about 2:3. In some embodiments, the mass
ratio of the at least one calcium salt to the at least one
phosphate-binding magnesium salt is between about 5:4 and about
4:5. In some embodiments, the mass ratio of the at least one
calcium salt to the at least one phosphate-binding magnesium salt
is about 1:1. In some embodiments, the mass ratio of the at least
one calcium salt to the at least one phosphate-binding magnesium
salt is about 10:9.
[0010] In some embodiments, the at least one calcium salt comprises
calcium acetate, and the at least one magnesium salt comprises
magnesium glycinate.
[0011] In some embodiments, the therapeutically effective dose of
calcium acetate is about 340 mg and the therapeutically effective
dose of magnesium glycinate is about 300 mg,
[0012] In another aspect, the present invention provides a
composition suitable for treating hyperphosphatemia containing a
therapeutically effective dose of at least one phosphate-binding
magnesium salt, wherein the at least one phosphate-binding
magnesium salt binds at least about 50 mg (e.g., at least about 75
mg, 100 mg, 125 mg, 150 mg, 175 mg) phosphate per gram. In some
embodiments, the at least one phosphate-binding magnesium salt
binds at least about 100 mg phosphate per gram.
[0013] In yet another aspect, the present invention provides a
composition suitable for treating hyperphosphatemia containing a
therapeutically effective dose of at least one phosphate-binding
magnesium salt, wherein the at least one phosphate-binding
magnesium salt is not magnesium carbonate. In some embodiments, the
at least one phosphate-binding magnesium salt binds at least about
50 mg (e.g., at least about 75 mg, 100 mg, 125 mg, 150 mg, 175 mg)
phosphate per gram.
[0014] In some embodiments, the at least one phosphate-binding
magnesium salt is selected from the group consisting of magnesium
aminobutyrate, magnesium arginate, magnesium aspartate, magnesium
betainate, magnesium carnitinate, magnesium glycinate, magnesium
hydroxide, magnesium lysinate, magnesium oxide, magnesium
propionate, and combination thereof.
[0015] In some embodiments, the therapeutically effective dose of
at least one phosphate-binding magnesium salt contains about 20 mg
to 1200 mg magnesium. In some embodiments, the therapeutically
effective dose of at least one phosphate-binding magnesium salt
contains less than about 1200 mg magnesium.
[0016] In some embodiments, the composition further contains a
calcium salt. In some embodiments, the calcium salt is present in
an amount that provides about 20 mg to 1200 mg calcium. In some
embodiments, the calcium salt is present in an amount that provides
less than 2000 mg calcium. In some embodiments, the calcium salt is
present in an amount that provides less than 600 mg calcium.
[0017] In still another aspect, the present invention provides a
composition suitable for treating hyperphosphatemia consisting
essentially of a calcium salt and a phosphate-binding magnesium
salt. In some embodiments, the calcium salt is selected from the
group consisting of calcium acetate, calcium aceturate, calcium
adipate, calcium alaninate, calcium alginate, calcium
aminobutyrate, calcium arginate, calcium ascorbate, calcium
aspartate, calcium benzoate, calcium besylate, calcium betainate,
calcium bromide, calcium buteprate, calcium butyrate, calcium
caproate, calcium carbesilate, calcium carbonate, calcium
carboxymethylcellulose, calcium carnitinate, calcium chloride,
calcium ciclotate, calcium citrate, calcium cypionate, calcium
enanthate, calcium esylate, calcium ethandisulfonate, calcium
formate, calcium fumarate, calcium glucarate, calcium gluceptate,
calcium gluconate, calcium glucuronate, calcium glutamate, calcium
glycinate, calcium hippurate, calcium hyclate, calcium hydroxide,
calcium iodide, calcium isethionate, calcium lactate, calcium
lactobionate, calcium levulinate, calcium lysinate, calcium malate,
calcium rnaleate, calcium mesylate, calcium metilsulfate, calcium
methylsulfate, calcium naphthoate, calcium napsylate, calcium
nicotinate, calcium nitrate, calcium oleate, calcium orotate,
calcium oxide, calcium oxoglurate, calcium pamoate, calcium
pantothenate, calcium picolinate, calcium pivalate, calcium
polygalacturonate, calcium propionate, calcium sorbate, calcium
steaglate, calcium stearate, calcium stearyl-2-lactylate, calcium
succinate, calcium sulfate, calcium sulfite, calcium tartrate,
calcium tebutate, calcium tosylate, calcium triflutate, calcium
xinafoate, and combination thereof. In some embodiments, the
phosphate-binding magnesium salt is selected from the group
consisting of magnesium aminobutyrate, magnesium arginate,
magnesium aspartate, magnesium betainate, magnesium carnitmate,
magnesium glycinate, magnesium hydroxide, magnesium lysinate,
magnesium oxide, magnesium propionate, and combination thereof. In
some embodiments, the calcium salt is calcium acetate, and the
phosphate-binding magnesium salt is magnesium glycinate.
[0018] In some embodiments, the mass ratio of the calcium salt to
the phosphate-binding magnesium salt is between about 100:1 and
about 1:100. In some embodiments, the mass ratio of the calcium
salt to the phosphate-binding magnesium salt is between about 10:1
and about 1:10. In some embodiments, the mass ratio of the calcium
salt to the phosphate-binding magnesium salt is between about 3:1
and about 1:3. In some embodiments, the mass ratio of the calcium
salt to the phosphate-binding magnesium salt is between about 2:1
and about 1:2. In some embodiments, the mass ratio of the calcium
salt to the phosphate-binding magnesium salt is between about 3:2
and about 2:3. In some embodiments, the mass ratio of the calcium
salt to the phosphate-binding magnesium salt is between about 5:4
and about 4:5. In some embodiments, the mass ratio of the calcium
salt to the phosphate-binding magnesium salt is about 1:1. In some
embodiments, the mass ratio of the calcium salt to the
phosphate-binding magnesium salt is about 10:9.
[0019] In some embodiments, the phosphate-binding magnesium salt is
present in an amount that provides about 20 mg to 1200 mg
magnesium. In some embodiments, the phosphate-binding magnesium
salt is present in an amount that provides less than 1200 mg
magnesium. In some embodiments, the calcium salt is present in an
amount that provides about 20 mg to 1200 mg calcium. In some
embodiments, the calcium salt is present in an amount that provides
less than 2000 mg (e.g., less than about 1800 mg, less than about
1600 mg, less than about 1400 mg, less than about 1200 mg, less
than about 1000 mg, less than about 800 mg, less than about 600 mg,
less than about 400 mg, less than about 200 mg) calcium.
[0020] Inventive compositions according to the invention can be
formulated for oral administration. In some embodiments, inventive
compositions are formulated as a nutritional supplement. In some
embodiments, inventive compositions of the invention can be in a
form of a tablet, a cachet, a hard gelatin capsule, a soft gelatin
capsule, a lozenge, suspension, or a bead.
[0021] In some embodiments, inventive compositions further contain
an enteric coating. In some embodiments, the enteric coating
contains acetyltributyl citrate, carbomers, cellulose acetate
phthalate, cellulose acetate succinate, ethyl cellulose, guar gum,
hypromellose acetate succinate, hypromellose phthalate,
polymethacrylates, polyvinyl acetate phthalate, shellac, tributyl
citrate, triethyl citrate, white wax and/or zein
[0022] In some embodiments, compositions of the invention further
include one or more pharmaceutically acceptable excipients. In some
embodiments, pharmaceutically acceptable excipients suitable for
the invention include starch, a gum, an alginate, a silicate,
dextrose, gelatin, lactose, mannitol, sorbitol, sucrose,
tragacanth, cellulose, methyl cellulose, microcrystalline
cellulose, a methylhydroxybenzoate, a propylhydroxybenzoate,
polyvinylpyrrolidone and/or talc.
[0023] The present invention further provides methods of treating
hyperphosphatemia by administering to a subject in need of
treatment any one of the compositions described herein.
[0024] In one aspect, the present invention provides a method of
treating hyperphosphatemia comprising administering to a subject in
need of treatment a calcium salt and a phosphate-binding magnesium
salt. In some embodiments, the phosphate-binding magnesium salt
binds at least about 50 mg phosphate per gram. In some embodiments,
the phosphate-binding magnesium salt is not magnesium
carbonate.
[0025] In some embodiments, the calcium salt is administered in an
amount that provides about 20 mg to 1200 mg of calcium per dose. In
some embodiments, the calcium salt is administered in an amount
that provides less than about 600 mg calcium per dose. In some
embodiments, the calcium salt is administered in an amount that
provides less than about 2000 mg (e.g., less than about 1800 mg,
less than about 1600 mg, less than about 1400 mg, less than about
1200 mg, less than about 1000 tug, less titan about 800 mg, less
than about 600 mg, less than about 400 mg, less than about 200 mg)
calcium per day.
[0026] In some embodiments, the phosphate-binding magnesium salt is
administered in an amount that provides about 20 mg to 1200 mg
magnesium per dose. In some embodiments, the phosphate-binding
magnesium salt is administered in an amount that provides less than
about 1200 mg magnesium per dose. In some embodiments, the
phosphate-binding magnesium salt is administered in an amount that
provides less than about 4000 mg (e.g., less than about 3500 mg,
less than about 3000 mg, less than about 2500 mg, less than about
2000 mg, less than about 1500 mg, or less than about 1000 mg)
magnesium per day.
[0027] In some embodiments, the calcium salt and phosphate-binding
magnesium salt are administered four times a day. In some
embodiments, the calcium salt and phosphate-binding magnesium salt
are administered three times a day. In some embodiments, the
calcium salt and phosphate-binding magnesium salt are administered
twice a day. In some embodiments, the calcium salt and
phosphate-binding magnesium salt are administered once daily.
[0028] In some embodiments, the calcium salt and phosphate-binding
magnesium salt are administered orally.
[0029] In some embodiments, the phosphate-binding magnesium salt is
administered with an enteric coating. In some embodiments, the
enteric coating contains acetyltributyl citrate, carbomers,
cellulose acetate phthalate, cellulose acetate succinate, ethyl
cellulose, guar gum, hypromellose acetate succinate, hypromellose
phthalate, polymethacrylates, polyvinyl acetate phthalate, shellac,
tributyl citrate, triethyl citrate, white wax and/or zein.
[0030] In some embodiments, the calcium salt and phosphate-binding
magnesium salt are administered simultaneously. In some
embodiments, the calcium salt and phosphate-binding magnesium salt
are administered sequentially.
[0031] In some embodiments, the calcium salt is selected from the
group consisting of calcium acetate, calcium aceturate, calcium
adipate, calcium alaninate, calcium alginate, calcium
aminobutyrate, calcium arginate, calcium ascorbate, calcium
aspartate, calcium benzoate, calcium besylate, calcium betainate,
calcium bromide, calcium buteprate, calcium butyrate, calcium
caproate, calcium carbesilate, calcium carbonate, calcium
carboxymethylcellulose, calcium camitinate, calcium chloride,
calcium ciclotate, calcium citrate, calcium cypionate, calcium
enanthate, calcium esylate, calcium ethandisulfonate, calcium
formate, calcium fumarate, calcium glucarate, calcium gluceptate,
calcium gluconate, calcium glucuronate, calcium glutamate, calcium
glycinate, calcium hippurate, calcium hyclate, calcium hydroxide,
calcium iodide, calcium isethionate, calcium lactate, calcium
lactobionate, calcium levulinate, calcium lysinate, calcium malate,
calcium maleate, calcium mesylate, calcium metilsulfate, calcium
methylsulfate, calcium naphthoate, calcium napsylate, calcium
nicotinate, calcium nitrate, calcium oleate, calcium orotate,
calcium oxide, calcium oxoglurate, calcium pamoate, calcium
pantothenate, calcium picolinate, calcium pivalate, calcium
polygalacturonate, calcium propionate, calcium sorbate, calcium
steaglate, calcium stearate, calcium stearyl-2-lactylate, calcium
succinate, calcium sulfate, calcium sulfite, calcium tartrate,
calcium tebutate, calcium tosylate, calcium triflutate, calcium
xinafoate, and combination thereof.
[0032] In some embodiments, the phosphate-binding magnesium salt is
selected from the group consisting of magnesium aminobutyrate,
magnesium arginate, magnesium aspartate, magnesium betainate,
magnesium carnitinate, magnesium glycinate, magnesium hydroxide,
magnesium lysinate, magnesium oxide, magnesium propionate, and
combination thereof
[0033] In some embodiments, the calcium salt and phosphate-binding
magnesium salt are administered at a mass ratio between about 100:1
and about 1:100. In some embodiments, the calcium salt and
phosphate-binding magnesium salt are administered at a mass ratio
between about 10:1 and about 1:10. In some embodiments, the calcium
salt and phosphate-binding magnesium salt are administered at a
mass ratio between about 3:1 and about 11:3. In some embodiments,
the calcium salt and phosphate-binding magnesium salt are
administered at a mass ratio between about 2:1 and about 1:2. In
some embodiments, the calcium salt and phosphate-binding magnesium
salt are administered at a mass ratio between about 3:2 and about
2:3. In some embodiments, the calcium salt and phosphate-binding
magnesium salt are administered at a mass ratio between about 5:4
and about 4:5. In some embodiments, the calcium salt and
phosphate-binding magnesium salt are administered at a mass ratio
of about 1:1. In some embodiments, the calcium salt and
phosphate-binding magnesium salt are administered at a mass ratio
of about 10:9.
[0034] In some embodiments, the calcium salt is calcium acetate,
and the phosphate-binding magnesium salt is magnesium glycinate. In
some embodiments, the calcium acetate is administered at a dose of
about 340 mg and the magnesium glycinate is administered at a dose
of about 300 mg.
[0035] In yet another aspect, the present invention provides a
method of treating hyperphosphatemia by administering to a subject
in need of treatment a phosphate-binding magnesium salt, wherein
the phosphate-binding magnesium salt binds at least about 50 mg
phosphate per gram.
[0036] In still another aspect, the present invention provides a
method of treating hyperphosphatemia by administering to a subject
in need of treatment a phosphate-binding magnesium salt, wherein
the phosphate-binding magnesium salt is not magnesium
carbonate.
[0037] In some embodiments, the phosphate-binding magnesium salt is
administered in an amount that provides about 20 mg to 1200 mg
magnesium per dose. In some embodiment, the phosphate-binding
magnesium salt is administered in an amount that provides less than
about 1200 mg magnesium per dose. In some embodiments, the
phosphate-binding magnesium salt is administered in an amount that
provides less than about 4000 mg (e.g., less than about 3500 mg,
less than about 3000 mg, less than about 2500 mg, less than about
2000 mg, less than about 1500 mg, or less than about 1000 mg)
magnesium per day.
[0038] In some embodiments, the phosphate-binding magnesium salt is
administered four times a day. In some embodiments, the
phosphate-binding magnesium salt is administered three times a day.
In some embodiments, the phosphate-binding magnesium salt is
administered twice a day. In some embodiments, the
phosphate-binding magnesium salt is administered once daily.
[0039] In some embodiments, the phosphate-binding magnesium salt is
administered orally. In some embodiments, the phosphate-binding
magnesium salt is administered in a form of a tablet, a cachet, a
hard gelatin capsule, a soft gelatin capsule, a lozenge,
suspension, or a bead.
[0040] In some embodiments, the phosphate-binding magnesium salt is
administered with an enteric coating. In some embodiments, a
suitable enteric coating contains acetyltributyl citrate,
carbomers, cellulose acetate phthalate, cellulose acetate
succinate, ethyl cellulose, guar gum, hypromellose acetate
succinate, hypromellose phthalate, polymethacrylates, polyvinyl
acetate phthalate, shellac, tributyl citrate, triethyl citrate,
white wax and/or zein.
[0041] In some embodiments, the phosphate-binding magnesium salt is
administered in combination with another phosphate binder (e.g., a
calcium salt).
[0042] In some embodiments, the present invention can be used to
treat a subject in need of treatment for chronic kidney disease
and/or end-stage renal disease. In some embodiments, the present
invention can be used to treat a subject in need of treatment for
one or more disorders of phosphate metabolism and/ or impaired
phosphate transport function.
[0043] In this application, the use of "or" means "and/or" unless
stated otherwise. As used in this application, the term "comprise"
and variations of the term, such as "comprising" and "comprises,"
are not intended to exclude other additives, components, integers
or steps. As used in this application, the terms "about" and
"approximately" are used as equivalents. Any numerals used in this
application with or without about/approximately are meant to cover
any normal fluctuations appreciated by one of ordinary skill in the
relevant art. In certain embodiments, the term "approximately" or
"about" refers to a range of values that fall within 25%, 20%, 19%,
18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%,
4%, 3%, 2%, 1%, or less in either direction (greater than or less
than) of the stated reference value unless otherwise stated or
otherwise evident from the context (except where such number would
exceed 100% of a possible value).
[0044] Other features, objects, and advantages of the present
invention are apparent in the detailed description, drawings and
claims that follow. it should be understood, however, that the
detailed description, the drawings, and the claims, while
indicating embodiments of the present invention, are given by way
of illustration only, not limitation. Various changes and
modifications within the scope of the invention will become
apparent to those skilled in the art
DETAILED DESCRIPTION OF THE INVENTION
[0045] The present invention provides compositions and methods for
removing phosphate from a subject based on phosphate-binding
magnesium salts. In some embodiments, the present invention
provides compositions and methods for treating hyperphosphatemia
using a phosphate-binding magnesium salt or, a combination of
phosphate-binding magnesium and calcium salts.
[0046] Various aspects of the invention are described in detail in
the following sections. The use of sections is not meant to limit
the invention. Each section can apply to any aspect of the
invention. In this application, the use of "or" means "and/or"
unless stated otherwise.
Phosphate-Binding Magnesium Salts
[0047] The present invention is, in part, based on the discovery of
the unexpected unique features of the phosphate-binding ability of
magnesium salts. It was common chemical knowledge that, like many
metals (e.g., calcium), the divalent cations of magnesium are
capable of forming highly insoluble salts with the phosphate anion
in aqueous solutions. However, unlike calcium, the effort of
developing therapeutic phosphate-binders based on magnesium salts
was not successful before the present invention. As described
below, the present inventors discovered that the ability of various
magnesium salts to bind phosphate under a condition simulating
small intestinal fluid (SW) is surprisingly different than calcium
salts, It was a chemical dogma and theory that if a salt of
metallic cations that is more soluble in water than is the
corresponding phosphate salt, an insoluble phosphate salt will form
when that salt is mixed into a solution containing phosphate. For
example, the solubility of calcium chloride in 20.degree. C. water
is 745 g/L and the solubility of calcium phosphate is 20mg/L.
Therefore, calcium chloride is 37250 times more soluble in water.
When calcium chloride is mixed in water with phosphate, an
insoluble calcium phosphate precipitate forms as expected. The
solubility of magnesium chloride is 546 g/L, in water, and the
solubility of magnesium phosphate is 0.26 m/L, Therefore, magnesium
chloride is 2,100,000 times more soluble in water than magnesium
phosphate, However, totally unexpectedly and unlike calcium, when a
solution of magnesium chloride was mixed with a phosphate solution
simulating small intestinal fluid (SIF), no insoluble magnesium
phosphate precipitate forms. As described in the Examples section,
upon testing numerous magnesium salts for their ability to form
insoluble magnesium phosphate in a solution similar to SIF, the
inventors of the present application discovered that only a few
magnesium salts would effectively precipitate phosphate from SIF.
Result from each magnesium salt was unexpected.
[0048] In addition, the present inventors further discovered that
magnesium salts and calcium salts may interact differently with
stomach acid which contains an overwhelming amount of HCl. As
described in the Examples section, certain active magnesium salts
(e.g., magnesium oxide or hydroxide) may react with stomach acid
(HCl) to form magnesium chloride (which, as described above, would
not be able to precipitate phosphate in SW) and thus lose their
ability to precipitate phosphate in SIF (see, Example 3).
Therefore, it is desirable to enteric coat magnesium salts, in
particular, those magnesium salts that are capable of reacting with
stomach acid (HCl) (referred to as "active magnesium salts" in this
application) such that magnesium salts are protected from stomach
acids. Unlike magnesium, calcium salts typically will not lose its
ability to precipitate phosphate in SIF after reacting with the
stomach acid (HCl) because converted calcium chloride, as described
above, readily precipitates phosphate from SIF. Therefore, any
calcium salt (acetate, carbonate, etc) absent any enteric coating
should still be an effective phosphate binder in humans.
[0049] As used herein, the term "phosphate-binding magnesium salts"
refers to any magnesium-containing salts that are capable of
binding, precipitating, and/or removing phosphate from a mammalian
subject under a physiological condition (e.g., in small intestinal
fluid) with or without an enteric coating. As used herein, the term
"enteric coating" or "enteric film" refers to a barrier applied to,
for example, oral medication containing magnesium salts that
controls the location in the digestive system where the medication
is absorbed. Typically, enteric coatings prevent release of
medication before it reaches the small intestine. In some
embodiments, enteric coatings suitable for the present invention
include surface coatings that are stable at the highly acidic pH
(e.g., pH 3) found in the stomach, but dissolve quickly at a less
acidic (relatively more basic) pH (e.g., (above pH 5.5). In some
embodiments, phosphate-binding magnesium salts suitable for the
invention include magnesium-containing salts that bind at least
about 25 mg (e.g., at least about 30 mg, 40 mg, 50 mg, 60 mg, 70
mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg,
160 mg, 170 mg, 180 mg, 190 mg, or 200 mg) phosphate per gram of
magnesium salt. In some embodiments, the phosphate-binding capacity
of a magnesium salt can be characterized using various
phosphate-binding assays known in the art. In some embodiments, the
phosphate-binding capacity of a magnesium salt is characterized in
a solution simulating SIF. Exemplary phosphate-binding assays in
solutions simulating SIF are described in the Example sections
below. Additional phosphate-binding assays are described in
Rosenbaum et al. Nephrol. Dial. Transplant. 12:961-964 (1997); and
Lowry K. Lopez J. Biol. Chem. 162:421-428 (1946), the teachings of
which are incorporated by reference herein.
[0050] Specific phosphate binding capacity of exemplary magnesium
salts are described in Example 2 (see Tables 2-5).
[0051] In some embodiments, phosphate-binding magnesium salts
suitable for the invention include those magnesium salts that bind
more than 25 mg phosphate per gram. Such exemplary
phosphate-binding magnesium salts include, but are not limited to,
magnesium aminobutyrate, magnesium arginate, magnesium aspartate,
magnesium betainate, magnesium carnitinate, magnesium glycinate,
magnesium hydroxide, magnesium lysinate, magnesium oxide, magnesium
propionate, and magnesium tartrate.
[0052] In some embodiments, phosphate-binding magnesium salts
suitable for the invention include those magnesium salts that bind
more than 50 mg phosphate per gram. Such exemplary
phosphate-binding magnesium salts include, but are not limited to,
magnesium aminobutyrate, magnesium arginate, magnesium aspartate,
magnesium betainate, magnesium carnitinate, magnesium glycinate,
magnesium hydroxide, magnesium lysinate, magnesium oxide, and
magnesium propionate.
[0053] In some embodiments, phosphate-binding magnesium salts
suitable for the invention include those magnesium salts that bind
more than 100 mg phosphate per gram. Such exemplary
phosphate-binding magnesium salts include, but are not limited to,
magnesium arginate, magnesium betainate, magnesium carnitinate,
magnesium glycinate, magnesium hydroxide, magnesium lysinate, and
magnesium oxide.
[0054] As described in the Examples section, certain
phosphate-binding magnesium salts identified by the present
inventors have much higher phosphate binding capacity than those
existing commercial phosphate binders, such as PhosLo.RTM. (calcium
acetate) and Renagel.RTM. (sevelamer hydrochloride) (see Example
2). Thus, the present invention provides phosphate-binding
magnesium salts that can be used for improved and more effective
therapies for hyperphosphatemia.
Phosphate-Binding Calcium Salts
[0055] In some embodiments, magnesium salts can be used in
combination with phosphate-binding calcium salts. Exemplary calcium
salts suitable for the present invention include, but are not
limited to, calcium acetate (Phosex.RTM., PhosLo.RTM.), calcium
aceturate, calcium adipak, calcium alaninate, calcium alginate,
calcium aminobutyrate, calcium arginate, calcium ascorbate
(Calcichew.RTM., Titralac.RTM.), calcium aspartate, calcium
benzoate, calcium besylate, calcium betainate, calcium bromide,
calcium buteprate, calcium butyrate, calcium caproate, calcium
carbesilate, calcium carbonate, calcium carboxymethylcellulose,
calcium carnitinate, calcium chloride, calcium ciclotate, calcium
citrate, calcium cypionate, calcium enanthate, calcium esylate,
calcium ethandisulfonate, calcium formate, calcium fumarate,
calcium glucarate, calcium gluceptate, calcium gluconate, calcium
glucuronate, calcium glutamate, calcium glycinate, calcium
hippurate, calcium hyclate, calcium hydroxide, calcium iodide,
calcium isethionate, calcium lactate, calcium lactobionate, calcium
levulinate, calcium lysinate, calcium malate, calcium maleate,
calcium mesylate, calcium metilsulfate, calcium methylsulfate,
calcium naphthoate, calcium napsylate, calcium nicotinate, calcium
nitrate, calcium oleate, calcium orotate, calcium oxide, calcium
oxoglurate, calcium pamoate, calcium pantothenate, calcium
picolinate, calcium pivalate, calcium polygalacturonate, calcium
propionate, calcium sorbate, calcium steaglate, calcium stearate,
calcium stearyl-2-lactylate, calcium succinate, calcium sulfate,
calcium sulfite, calcium tartrate, calcium tebutate, calcium
tosylate, calcium triflutate, calcium xinafoate, and mixtures or
combination thereof
[0056] The molecule weight and percentage of calcium in certain
exemplary calcium salts suitable for the present invention are
shown in Table 1.
TABLE-US-00001 TABLE 1 Exemplary calcium salts suitable for the
invention Salt of calcium MW Percent Ca Acetate 158.17 25.34
Alginate 195.16 10.27 Ascorbate 390.32 10.27 Carbonate 100.09 40.04
Carboxymethylcellulose 257.23 7.79 Carnitinate 362.5 11.06 Chloride
110.98 36.11 Citrate 498.43 24.12 Gluconate 430.37 9.31 Lactate
218.22 18.37 Levulinate 270.29 14.83 Orotate 350.3 11.4 Oxide 56.08
71.47 Pantothenate 476.54 8.41 Propionate 186.22 21.52 D-Saccharate
(D-glucarate) 248.2 16.15 Stearate 607.03 6.60 Stearyl-2 lactylate
895.28 4.48 Succinate 156.15 25.67 Sulfate 136.14 29.44 Sulfite
120.14 33.36 Tartrate 188.15 21.30
[0057] Phosphate-binding magnesium salts may also be used in
combination with various other phosphate-binding agents including,
but not limited to, phosphate-binding aluminium salts (e.g.,
aluminium hydroxide (Alucaps.RTM.)), lanthanum salts (e.g.,
lanthanum carbonate (Fosrenol.RTM.)), polymers (e.g., sevelamer
(Renagel.RTM., Renvela.RTM.)), and chitosan.
Treatment of Hyperphosphatemia
[0058] Phosphate-binding magnesium salts described herein can be
used to bind and/or remove phosphate from a mammalian subject. In
particular, phosphate-binding magnesium salts described herein can
be used to treat hyperphosphatemia. As used herein, the term
"hyperphosphatemia" refers to a higher than normal blood level of
phosphorous. In human adults, the normal range for blood
phosphorous is approximately 2.5-4.5 mg/dL (i.e., 2.5-4.5 mg/100
mL). Typically, an individual with hyperphosphatemia condition has
fasting serum phosphorus concentration higher than 5.0 mg/dL (e.g.,
higher than 5.5 mg/dL, 6.0 mg/dL, 6,5 mg/dL, or 7.0 mg/dL). Methods
for measuring phosphate concentrations are well known in the art.
For example, phosphate concentrations can be measured by the method
of Lowry and Lopez, J. Biol. Chem. 162: 421-428. The
hyperphosphatemia 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.
[0059] Hyperphosphatemia is associated with various diseases or
medical conditions including, but not limited to, diseases
associated with inadequate renal function such as, for example,
chronic kidney disease and/or end-stage renal disease,
hypoparathyroidism, and other disorders of phosphate metabolism
and/or impaired phosphate transport function.
[0060] Typically, a method of treating hyperphosphatemia includes
administering to a subject in need of treatment a therapeutically
effective amount of a phosphate-binding magnesium salt. In some
embodiments, a method of treating hyperphosphatemia includes
administering to a subject in need of treatment a therapeutically
effective amount of at least one phosphate binding magnesium salt
and at least one phosphate-binding calcium salt. As used herein,
the term "therapeutically effective amount" refers to an amount
effective to reduce or control serum phosphate level or to treat,
prevent, and/or delay the onset of the symptom(s) caused by
hyperphosphatemia when administered in a single dose or in a series
of doses separated by appropriate time intervals, such as hours or
days, to a subject suffering from or susceptible to a disease,
disorder, and/or condition associated with hyperphosphatemia. A
therapeutically effective amount is commonly administered in a
dosing regimen that may comprise multiple unit doses. An
appropriate unit dose within an effective dosing regimen is
referred to as "therapeutically effective dose."
[0061] As used herein, an "individual," "patient" or "subject"
being treated includes a human or a. non-human such as, a non-human
mammalian subject including, but not limited to, a bovine, cat,
dog, ferret, gerbil, goat, guinea pig, hamster, horse, mouse,
nonhuman primate, pig, rabbit, rat, or sheep. As used herein, a
"subject susceptible to" a disease, disorder and/or condition
associated with hyperphosphatemia refers to an individual at risk
of developing hyperphosphatemia or to a patient reporting one or
more of the physiological symptoms of hyperphosphatemia, even
though a diagnosis of hyperphosphatemia may not have been made.
[0062] As used herein, the term "reduce," "decrease," or
grammatical equivalents, indicate values that are relative to a
baseline measurement, such as a measurement in the same individual
prior to initiation of the treatment described herein, or a
measurement in a control individual (or multiple control
individuals) in the absence of the treatment described herein. A
"control individual" is an individual afflicted with the same
condition of hyperphosphatemia as the individual being treated.
[0063] As used herein, the term "treat," "treatment," or "treating"
refers to any method used to partially or completely alleviate,
ameliorate, relieve, inhibit, prevent, delay onset of, reduce
severity of and/or reduce incidence of one or more symptoms or
features of hyperphosphatemia or of a particular disease, disorder,
and/or condition underlying hyperphosphatemia. Treatment may be
administered to a subject who does not exhibit signs of a disease
and/or exhibits only early signs of the disease for the purpose of
decreasing the risk of developing pathology associated with the
disease. For prophylactic benefit, a composition of the invention
may be administered to a patient at risk of developing
hyperphosphatemia or to a patient reporting one or more of the
physiological symptoms of hyperphosphatemia, even though a
diagnosis of hyperphosphatemia may not have been made.
[0064] The actual amount effective for a particular application
will depend on the condition being treated (e.g., the disease or
disorder and its severity, and the age and weight of the patient to
be treated) and the route of administration. Determination of an
effective amount is well within the capabilities of those skilled
in the art, especially in light of the disclosure herein. For
example, the effective amount for use in humans can be determined
from animal models. For example, a dose for humans can be
formulated to achieve circulating and/or gastrointestinal
concentrations that have been found to be effective in animals.
Pharmaceutical Compositions
[0065] Phosphate-binding magnesium salts may be formulated in a
pharmaceutical composition as described herein. When a magnesium
salt is used in combination with one or more other
phosphate-binding agents, the magnesium salt and the one ore more
other phosphate-binding agents can be formulated into one
composition or into separate compositions. In some embodiments, a
pharmaceutical composition according to the invention contains at
least one magnesium salt described herein and at least one calcium
salt described herein. Magnesium salt and calcium salt may be
combined at various mass or molar ratios. For example, the mass or
molar ratio of the calcium salt to the magnesium salt can be
between about 100:1 and about 1:100 (e.g., between about 50:1 and
about 1:50, between about 20:1 and about 1:20, between about 10:1
and about 1:10, between about 5:1 and about 1:5, between about 3:1
and about 1:3, between about 2:1 and about 1:2, between about 3:2
and about 2:3, between about 5:4 and about 4:5). In some
embodiments, the mass or molar ratio of the calcium salt to the
magnesium salt is about 1:1. In some embodiments, the mass or molar
ratio of the calcium salt to the magnesium salt is about 10:9. In
some embodiments, the mass or molar ratio of the calcium salt to
the magnesium salt is about 9:10.
[0066] Typically, a composition according to the invention is
formulated to contain a therapeutically effective amount or dose of
magnesium or calcium salt. The actual amount or dose effective for
a particular application will depend on the condition being treated
(e.g., the disease or disorder and its severity, and the age and
weight of the patient to be treated) and the route of
administration. Determination of an effective amount or dose is
well within the capabilities of those skilled in the art,
especially in light of the disclosure herein. For example, the
effective amount or dose for use in humans can be determined from
animal models. In some embodiments, a dose for humans can be
formulated to achieve circulating and/or gastrointestinal
concentrations that have been found to be effective in animals.
[0067] In some embodiments, a therapeutically effective dose of a
calcium salt according to the invention may contain about 20 mg to
1200 mg of calcium (e.g., about 20 mg to about 1000 mg of calcium,
about 20 mg to about 800 mg of calcium, about 20 mg to about 600 mg
of calcium, about 20 mg to about 400 mg of calcium, about 20 mg to
about 200 mg of calcium, about 100 mg to about 300 mg of calcium,
about 100 mg to about 500 mg of calcium, about 100 mg to about 700
mg of calcium, about 100 mg to about 900 mg of calcium). In some
embodiments, a therapeutically effective dose of a calcium salt
according to the invention contains less than about 2000 mg (e.g.,
less than about 1800 mg, less than about 1600 mg, less than about
1.400 mg, less than about 1200 mg, less than about 1000 mg, less
than about 800 mg, less than about 600 mg, less than about 500 mg,
less than about 400 mg, less than about 300 mg, less than about
200) of calcium. In some embodiments, a therapeutically effective
dose of a magnesium salt according to the invention may contain
about 20 mg to 1200 mg of magnesium (e.g., about 20 mg to about
1000 mg of magnesium, about 20 mg to about 800 mg of magnesium,
about 20 mg to about 600 mg of magnesium, about 20 mg to about 400
mg of magnesium, about 20 mg to about 200 mg of magnesium, about
100 mg to about 300 mg of magnesium, about 100 mg to about 500 mg
of magnesium, about 100 mg to about 700 mg of magnesium, about 100
mg to about 900 mg of magnesium). In some embodiments, a
therapeutically effective dose of a magnesium salt contains less
than about 1200 mg of magnesium (e.g., less than about 1000 mg of
magnesium, less than about 800 mg magnesium, less than about 600 mg
of magnesium, less than about 400 mg of magnesium, or less than
about 200 mg magnesium).
[0068] In some embodiments, compositions according to the
invention, when administered according to a suitable dosing
regimen, provide a therapeutically effective amount of calcium
ranging from about 60 mg to about 4000 mg (e.g., from about 80 mg
to about 3000, from about 1000 mg to about 2000 mg, from about 500
mg to about 1200 mg, from about 500 mg to about 1100 mg, from about
500 mg to about 1000 mg) per day. In some embodiments, compositions
according to the invention, when administered according to a
suitable dosing regimen, provide less than about 2000 mg (e.g.,
less than about 1800 mg, less than about 1600 mg, less than about
1400 mg, less than about 1200 mg, less than about 1000 mg, less
than about 800 mg, less than about 600 mg, less than about 400 mg,
or less than about 200 mg) calcium per day. In some embodiments,
compositions according to the invention, when administered
according to a suitable dosing regimen, provide a therapeutically
effective amount of magnesium ranging from about 60 mg to about
4000 mg (e.g., from about 80 mg to about 3000, from about 1000 mg
to about 2000 mg, from about 500 mg to about 1200 mg, from about
500 mg to about 1100 mg, from about 500 mg to about 1000 mg) per
day. In some embodiments, compositions according to the invention,
when administered according to a suitable dosing regimen, provide
more than about 500 mg (e.g., more than about 750 mg, more than
about 1000 mg, more than about 1250 mg, more than about 1500 mg,
more than about 1750 mg, or more than about 2000 mg) magnesium per
day. In some embodiments, compositions according to the invention,
when administered according to a suitable dosing regimen, provide
less than about 4000 mg (e.g., less than about 3500 mg, less than
about 3000 mg, less than about 2500 mg, less than about 200 mg,
less than about 1500 mg, or less than about 1000 mg) magnesium per
day.
[0069] Compositions according to the invention may be administered
four times a day, three times a day, twice a day, once daily, once
every other day, twice a week, or once a week. In some embodiments,
compositions according to the invention may be administered
together with a meat.
[0070] Typically, a composition of the invention further includes a
carrier. A carrier suitable for the invention is also referred to
as a pharmaceutically acceptable carrier, a carrier-diluent, or
excipient. A carrier may be a solid, semi-solid or liquid material
which acts as an excipient, medium, and/or vehicle for chitosan.
For example, a composition of the invention can be in a solid or
liquid medium. For example, phosphate-binding salts may be enclosed
within a carrier, such as a capsule, paper, sachet or other
container. In particular, a suitable carrier, excipient, or diluent
may be a starch, a gum, an alginate, a silicate, dextrose, gelatin,
lactose, mannitol, sorbitol, sucrose, tragacanth, cellulose, methyl
cellulose, microcrystalline cellulose, a methylhydroxybenzoate, a
propylhydroxybenzoate, polyvinylpyrrolidone or talc.
[0071] A composition of the invention can be formulated for
administration by injection, topically, orally, transdermally, or
rectally. In some embodiments, a composition of the present
invention is formulated for oral administration. For example, a
composition according to the invention may be in a form of a
cachet, a hard gelatin capsule, a soft gelatin capsule, an elixir,
a lozenge, a pill, a powder, a sachet, a sterile packaged powder, a
suspension, a syrup, a tablet, a capsule, solution, or emulsion, to
name but a few.
[0072] In some embodiments, a composition according to the
invention may contain an enteric coating or film. Such a
formulation or composition is also referred to as an "enterically
coated" formulation or composition. As used herein, the term
"enteric coating" or "enteric film" refers to a barrier applied to,
for example, oral medication that controls the location in the
digestive system where the medication is absorbed. Typically,
enteric coatings prevent release of medication before it reaches
the small intestine. In some embodiments, enteric coatings suitable
for the present invention include surface coatings that are stable
at the highly acidic pH (e.g., pH .about.3) found in the stomach,
but dissolve quickly at a less acidic (relatively more basic) pH
(e.g., (above pH 5.5). According to the present invention, an
enteric film or coating prevents dispersion of magnesium salt
and/or calcium salt in the acidic environment of the lumen of the
stomach. Materials suitable for enteric coatings include, but not
limited to, acetyltributyl citrate, carbomers, cellulose acetate
phthalate, cellulose acetate succinate, ethyl cellulose, fatty
acids, guar gum, hypromellose acetate succinate, hypromellose
phthalate, polymethacrylates, polyvinyl. acetate phthalate,
plastics, shellac, tributyl citrate, triethyl citrate, waxes (e.g.,
white wax), zein and combination thereof.
[0073] In some embodiments, a composition of the invention can be a
food, a drink, or a nutritional, food or dietary supplement. In one
embodiment, the composition is a nutritional supplement. As used
herein, "a nutritional supplement" is a preparation formulated to
supply nutrients (including, but not limited to, vitamins,
minerals, fatty acids or amino acids) that are missing or not
consumed in sufficient quantity in a person's or animal's diet. As
used in this application, a nutritional supplement is also referred
to as "a food supplement" or "a dietary supplement."
[0074] In some embodiments, the composition of the invention is a
nutritional supplement for a person's diet. The nutritional
supplement can be administered with or without meals and can be
administered once daily, twice daily, three times daily, once every
other day, twice a week, once a week, or at a variable intervals.
In some embodiments, the nutritional supplements can be
administered three times daily with meals. Supplements may be in
various forms including, for example, powders, liquids, syrups,
pills, encapsulated compositions, etc.
[0075] In some embodiments, the composition of the invention is a
nutritional supplement for an animal's diet, such as, a feed or pet
food used with another feed or pet food to improve the nutritive
balance or performance of the total, Contemplated supplements
include compositions that are fed undiluted as a supplement to
other feeds or pet foods, offered ad libitum with other parts of an
animal's ration that are separately available, or diluted and mixed
with an animal's regular feed or pet food to produce a complete
feed or pet food.
[0076] In another embodiment, a composition of the invention can be
a treat for animals. Treats include, for example, compositions that
are given to an animal to entice the animal to eat during a
non-meal time. Contemplated treats for canines include, for
example, dog bones. Treats may be nutritional, wherein the
composition comprises one or more nutrients, and may, for example,
have a composition as described above for food. Non-nutritional
treats encompass any other treats that are non-toxic.
[0077] Typically, phosphate-binding magnesium salts are present in
the composition at concentrations that do not impart an odor or
flavor that causes the intended animal to perceive the composition
to be unacceptable for consumption. In many instances, a desirable
odor and flavor can be achieved using aroma or flavor
enhancers.
[0078] In some embodiments, the percentage of the magnesium salt(s)
or the combined mass of magnesium and calcium slats, in a
composition of the invention is at least about 0.005% by weight of
the composition (e.g., at least about 0.1%, 0.5%, 1.0%, 1.5%, 2%,
2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 10%, 15%, 20%, 25%, 30% or higher).
In some embodiments, the percentage of magnesium and/or calcium
salts in a composition of the invention ranges from about 0.1% to
about 30% based on the weight of the composition. In some
embodiments, the percentage of magnesium and/or calcium salts in a
composition of the invention ranges from about 0.1% to about 10%
based on the weight of the composition. In some embodiments, the
percentage of magnesium and/or calcium salts in a composition of
the invention ranges from about 0.2% to about 5% based on the
weight of the composition. In some embodiments, the percentage of
magnesium and/or calcium salts in a composition of the invention
ranges from about 0.35% to about 1.0% based on the weight of the
composition.
[0079] The present invention, thus generally described, will be
understood more readily by reference to the following examples,
which are provided by way of illustration and are not intended to
be limiting of the present invention.
EXAMPLES
Example 1
Phosphate-Binding Assays
[0080] Exemplary stock solutions suitable for phosphate-binding
assays include the following: phosphate-binding solution ("PBS")
containing 10 mM KH2PO4, 30 mM Na2CO3, 80 mM NaCl, as described in
Rosenbaum et al. Nephrol. Dial. Transplant. 12:961-964 (1997);
acetate buffer ("AB") solution containing 0.1N acetic acid, 0.025N
sodium acetate, as described in Lowry & Lopez J. Biol. Chem.
162:421-428 (1946); ammonium molybdate ("AM") solution containing
1% ammonium molybdate in 0.05N H2SO4, as described in Lowry &
Lopez; ascorbic acid ("AA") solution containing 1% ascorbic acid in
H2O, as described in Lowry & Lopez.
[0081] In general, the phosphate-binding assay was conducted in
12.times.75 mm glass tubes. 4.0 mL PBS (which is a solution
simulating SIF) and 20 mg putative phosphate binder were added to a
glass tube and then mixed for 1 h at room temperature. 0.1 mL
supernatant was pipetted from this tube to a new test tube. 3.0 mL
AB, 0.3 mL AA and 0.3 mL AM solutions were added and O.D. were
measured at 700 nm after 10 minutes. The assay was shown to be
linear over the range used in this example.
[0082] The phosphate binding capacity was calculated as follows
(mcg stands for micrograms):
((O.D. of sample.times.95)/O.D. of standard).times.40=mcgPO4 left
in solution
((3800-mcgPO4 left).times.50)/1000=mgPO4 bound per gram of
phosphate binder
Example 2
Exemplary Phosphate-Binding Magnesium Salts
[0083] The phosphate binding capacity of various magnesium and
calcium salts were measured using the phosphate-binding assays
described in Example 1. Exemplary results were shown in Tables
2-5.
TABLE-US-00002 TABLE 2 Exemplary phosphate-binding results Sample
PO.sub.4 binding, mg/g PhosLo .RTM. 146.6 MgO 184.0 Mg(OH)2 176.2
MgCO3 19.0 MgSO4.cndot.7H2O 19.0 Mg citrate 16.3 CaCO3 10.9
TABLE-US-00003 TABLE 3 Exemplary phosphate-binding magnesium salts
Sample PO.sub.4 binding, mg/g PhosLo .RTM. 171 Renagel .RTM. 85 Mg
acetate 4 Mg adipate 6 Mg aminobutyrate 85 Mg arginate 121 Mg
ascorbate 4 Mg aspartate 50 Mg betainate 147 Mg carbonate 22 Mg
chloride 4 Mg citrate 15 Mg carnitinate 169 Mg formate 6 Mg
fumarate 4 Mg glycinate 176 Mg hydroxide 182 Mg lactate 15 Mg
lysinate 150 Mg maleate 15 Mg nicotinate 4 Mg orotate 20 Mg oxide
.gtoreq.190 Mg propionate 59 Mg stearate 15 Mg succinate 18 Mg
sulfate 9 Mg tartrate 28
[0084] Certain phosphate-binding results of Table 3 were calculated
to reflect the phosphate-binding capacity as follows.
TABLE-US-00004 TABLE 4 Exemplary phosphate-binding capacity mg
PO.sub.4 bound % Mg mg PO.sub.4 bound per g Mg Compound (or % Ca)
per g compound or Ca in compound Mg arginate 6.5 121 1862 Mg
betainate 9.5 147 1547 Mg glycinate 14.1 176 1248 Mg hydroxide 41.7
182 436 Mg lysinate 7.7 150 1948 Mg oxide 60.3 190 315 PhosLo .RTM.
(25.3% Ca) 171 676 (Ca acetate)
[0085] It can be seen that certain magnesium salts have high
phosphate-binding capacity. For example, 1 grain of Mg in some
magnesium salts (e.g., Mg lysinate) binds phosphate almost three
times as much as 1 gram of calcium in PhosLo.RTM. (Ca acetate)
does.
[0086] Additional results are shown in Table 5.
TABLE-US-00005 TABLE 5 Exemplary phosphate-binding capacity mg
PO.sub.4 bound mg PO.sub.4 bound Compound per g compound per g Mg
(or Ca) in compound PhosLo(R) 161 (636, per gram Ca) (Ca acetate)
Mg aminobutyrate 76 Mg arginate 118 1815 Mg betainate 141 1484 Mg
glycinate 177 1255 Mg lysinate 138 1792 Mg oxide 187 310 Mg malate
29
Example 3
Impact of Stomach Acid on the Phosphate-Binding Ability of Certain
Magnesium Salts
[0087] This experiment was conducted to demonstrate that stomach
acid can destroy the phosphate-binding activity of a normally
active magnesium salt. Specifically, 20 mg MgO was first reacted
with 100 .mu.L 10M HCl which simulates the overwhelmingly acidic
stomach environment. The reacted mixture were then tested for its
ability to bind phosphate in an phosphate-binding assay as
described above. As shown in Table 6, MgO, which normally has a
phosphate-binding capacity of about 188.5 mg/g, lost its ability to
bind phosphate after the reaction with 100 .mu.L 10M Similar
results were observed with Mg(OH)2.
TABLE-US-00006 TABLE 6 Exemplary results illustrating the impact of
stomach acid Sample PO.sub.4 binding, mg/g PhosLo .RTM. 148.8 MgO
188.5 20 mg MgO + 100 .mu.L 10M HCl 0 Mg(OH)2 179.0 20 mg
Mg(OH).sub.2 + 70 .mu.L 10M HCl 0
Example 4
Composition Containing Calcium Acetate and Magnesium Glycinate
[0088] This experiment was designed to show the therapeutic and
nutritional benefits provided by a composition of the invention
that contains both calcium and magnesium salts. Specifically, a
composition containing both calcium acetate and magnesium glycinate
was made by mixing PhosLo.RTM. (calcium acetate) and magnesium
glycinate at a mass ratio of approximately 1:1 (e.g., 300 mg Mg
glycinate and 340 mg Ca acetate). The phosphate binding ability of
the composition was determined by the phosphate-binding assay
described in Example 1 and exemplary results were shown in Table
7.
TABLE-US-00007 TABLE 7 Compound PO.sub.4 binding, mg/g PhosLo(R)
152 Mg glycinate 182 PhosLo:MgGlycinate::1:1 185
[0089] As shown in Table 7, the composition containing both
PhosLo.RTM. (calcium acetate) and magnesium glycinate binds
approximately 185 mg phosphate per gram, which is more effective
than PhosLo.RTM. alone (which binds approximately 152 tug phosphate
per grain) and comparable to Mg glycinate alone (which binds
approximately 182 mg phosphate per gram).
[0090] A therapeutic composition is made that contains 300 mg Mg
glycinate and 340 mg Ca acetate per dose. Under the existing
practice, a human patient typically takes four doses of PhosLo.RTM.
with each meal, three meals a day. Therefore, the patient ingests
approximately 2025 mg Ca a day, which would result in the binding
of approximately 1328 mg phosphate. If a patient instead takes four
doses of the therapeutic composition containing 300 mg Mg glycinate
and 340 mg Ca acetate per dose with each meal, three meals a day,
the patient would ingest about 1032 mg Ca (which binds about 677 mg
phosphate), and about 508 mg Mg (which binds about 635 mg
phosphate). Therefore, the composition containing 300 mg Mg
glycinate and 340 mg Ca acetate per dose would remove about 1312 mg
phosphate per day, similar to the amount of phosphate removed by
PhosLo.RTM. using the existing treatment method. However, a patient
treated with the composition containing 300 mg Mg glycinate and 340
mg Ca acetate will only ingest 1032 mg Ca per day, which is almost
only one half of the Ca amount ingested by a patient per day
treated by PhosLo.RTM.. Moreover, the composition containing 300 mg
Mg glycinate and 340 mg Ca acetate per dose provides 508 mg Mg per
day, a nutrient deficient in many individuals, while PhosLo.RTM.
provides 0 mg Mg. Therefore, a therapeutic composition based on a
combination of magnesium and calcium salts provides effective
phosphate-binding while significantly reducing calcium burdens in
patients and, at the same time, providing nutritional benefits.
Example 5
Preparation of an Oral Formulation with an Enteric Coating
[0091] An oral formulation that contains calcium acetate and
magnesium glycinate is prepared as follows. Calcium acetate,
magnesium glycinate, one excipient suitable for enteric coating,
one or more pharmaceutically acceptable excipients and other
appropriate ingredients (e.g., a lubricant) are mixed until a
degree of uniformity suitable for pharmaceutical formulation is
reached. The mixture is shaped into tablets or caplets. Tablets or
caplets are then coated with at least one excipient suitable for
enteric coating using standard methods.
Example 6
Treatment of Hyperphosphatemia
[0092] An oral formulation containing calcium acetate and magnesium
glycinate prepared as described in Example 5 is used to treat human
patients suffering from hyperphosphatemia. The first patient has a
serum phosphorus level between about 5.5 and about 7.5 mg/dL and
has not taken a phosphate binder. Two units of the formulation are
orally administered to the patient three times daily with meals.
The second patient has a serum phosphorus level between about 7.5
and about 9.0 mg/dL and has not taken a phosphate binder. Three
units of the same formulation are orally administered to the
patient three times daily with meals. The third patient has a serum
phosphorus level greater than about 9.0 mg/dL and has not taken a
phosphate binder. Four units of the formulation are orally
administered to the patient three times daily with meals. The
fourth patient has been taking one 667-mg calcium acetate tablet
per meal. One unit of the formulation is orally administered to the
fourth patient three times daily with meals, instead of the one
667-mg calcium acetate tablet per meal. The fifth patient has been
taking two 667-mg calcium acetate tablets per meal. Two units of
the formulation are orally administered to the patient three times
daily with meals, instead of the two 667-mg calcium acetate tablets
per meal. The sixth patient has been taking three 667-mg calcium
acetate tablets per meal. Three units of the formulation are orally
administered to the patient three times daily with meals, instead
of the three 667-mg calcium acetate tablets per meal.
[0093] In each of the above cases, the patient's serum phosphorus
level is reduced to and remains in the range from 3.5 to 5.5 mg/dL
after treatment according to the dosing regimen described above. A
dosing regimen can be maintained relatively unchanged when the
serum phosphorus level is within the range of 3.5 to 5.5 mg/dL.
EQUIVALENTS
[0094] The foregoing has been a description of certain non-limiting
embodiments of the invention. Those skilled in the art will
recognize, or be able to ascertain using no more than routine
experimentation, many equivalents to the specific embodiments of
the invention described herein. Those of ordinary skill in the art
will appreciate that various changes and modifications to this
description may be made without departing from the spirit or scope
of the present invention, as defined in the following claims.
[0095] in the claims articles such as "a," "an" and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention also includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process. Furthermore, it is to be understood that the invention
encompasses all variations, combinations, and permutations in which
one or more limitations, elements, clauses, descriptive terms,
etc., from one or more of the claims or from relevant portions of
the description are introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Furthermore, where the claims recite a
composition, it is to be understood that methods of using the
composition for any of the purposes disclosed herein are included,
and methods of making the composition according to any of the
methods of making disclosed herein or other methods known in the
art are included, unless otherwise indicated or unless it would be
evident to one of ordinary skill in the art that a contradiction or
inconsistency would arise. In addition, the invention encompasses
compositions made according to any of the methods for preparing
compositions disclosed herein.
[0096] Where elements are presented as lists, e.g., in Markush
group format, it is to be understood that each subgroup of the
elements is also disclosed, and any element(s) can be removed from
the group. It is also noted that the term "comprising" is intended
to be open and permits the inclusion of additional elements or
steps. It should be understood that, in general, where the
invention, or aspects of the invention, is/are referred to as
comprising particular elements, features, steps, etc., certain
embodiments of the invention or aspects of the invention consist,
or consist essentially of, such elements, features, steps, etc. For
purposes of simplicity those embodiments have not been specifically
set forth in haec verba herein. Thus for each embodiment of the
invention that comprises one or more elements, features, steps,
etc., the invention also provides embodiments that consist or
consist essentially of those elements, features, steps, etc.
[0097] Where ranges are given, endpoints are included. Furthermore,
it is to be understood that unless otherwise indicated or otherwise
evident from the context and/or the understanding of one of
ordinary skill in the art, values that are expressed as ranges can
assume any specific value within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates otherwise.
It is also to be understood that unless otherwise indicated or
otherwise evident from the context and/or the understanding of one
of ordinary skill in the art, values expressed as ranges can assume
any subrange within the given range, wherein the endpoints of the
subrange are expressed to the same degree of accuracy as the tenth
of the unit of the lower limit of the range.
[0098] In addition, it is to be understood that any particular
embodiment of the present invention may be explicitly excluded from
any one or more of the claims. Any embodiment, element, feature,
application, or aspect of the compositions and/or methods of the
invention can be excluded from any one or more claims. For purposes
of brevity, all of the embodiments in which one or more elements,
features, purposes, or aspects is excluded are not set forth
explicitly herein.
INCORPORATION OF REFERENCES
[0099] All publications and patent documents cited in this
application are incorporated by reference in their entirety to the
same extent as if the contents of each individual publication or
patent document were incorporated herein.
* * * * *