U.S. patent application number 15/346995 was filed with the patent office on 2017-06-01 for amide dendrimer compositions.
The applicant listed for this patent is GENZYME CORPORATION. Invention is credited to Pradeep K. DHAL, David J. HARRIS, Stephen Randall HOLMES-FARLEY, Chad C. HUVAL, Vitaly NIVOROZHKIN, Bruce SHUTTS.
Application Number | 20170152347 15/346995 |
Document ID | / |
Family ID | 39268976 |
Filed Date | 2017-06-01 |
United States Patent
Application |
20170152347 |
Kind Code |
A1 |
DHAL; Pradeep K. ; et
al. |
June 1, 2017 |
AMIDE DENDRIMER COMPOSITIONS
Abstract
Amide compounds, amide polymers, compositions including amide
compounds and amide polymers may be used to bind target ions, such
as phosphorous-containing compounds in the gastrointestinal tract
of animals. In some cases, amide compounds and amide polymers may
include a core derived from an amide polyol and an organic polyacid
or ester.
Inventors: |
DHAL; Pradeep K.; (Westford,
MA) ; HARRIS; David J.; (Lexington, MA) ;
HOLMES-FARLEY; Stephen Randall; (Arlington, MA) ;
HUVAL; Chad C.; (Grand Coteau, LA) ; NIVOROZHKIN;
Vitaly; (Boxborough, MA) ; SHUTTS; Bruce;
(Bolton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GENZYME CORPORATION |
Cambridge |
MA |
US |
|
|
Family ID: |
39268976 |
Appl. No.: |
15/346995 |
Filed: |
November 9, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14718244 |
May 21, 2015 |
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15346995 |
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14260917 |
Apr 24, 2014 |
9066972 |
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14718244 |
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13848968 |
Mar 22, 2013 |
8900560 |
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14260917 |
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12311362 |
Nov 23, 2009 |
8425887 |
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PCT/US2007/020852 |
Sep 26, 2007 |
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13848968 |
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60847905 |
Sep 29, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/785 20130101;
A61P 21/02 20180101; A61P 9/00 20180101; C08G 69/40 20130101; C08G
83/003 20130101; A61P 5/18 20180101; A61P 19/02 20180101; A61P 3/12
20180101; C07C 237/10 20130101; A61P 3/14 20180101; C07C 235/08
20130101; A61P 27/02 20180101; A61K 8/72 20130101; C08L 101/00
20130101; A61P 11/00 20180101; A61P 43/00 20180101; A61P 13/12
20180101 |
International
Class: |
C08G 69/40 20060101
C08G069/40 |
Claims
1-100. (canceled)
101. An amide polymer comprising: a) at least one amide compound or
residue thereof, said amide compound represented by the following
Formula I: ##STR00042## wherein n independently represents an
integer from 0-20; R independently represents a hydrogen radical, a
hydroxyl radical, --OR.sub.3, --R.sub.2OH, --R.sub.2OR.sub.3, or
C(O)N(R.sub.1).sub.2; R.sub.1 independently represents a hydrogen
radical, a hydroxyl radical, --OR.sub.3, or a branched or
unbranched, substituted C.sub.1-C.sub.10 alkyl radical wherein one
or more carbon atoms of said alkyl radical is partially or fully
substituted with --OH and/or --OR.sub.3 groups; R.sub.2
independently represents a substituted or unsubstituted, branched
or unbranched alkyl; and R.sub.3 is independently represented by
the following Formula II: ##STR00043## wherein p, q and r
independently represent an integer from 0-2; R.sub.4 independently
represents, ##STR00044## wherein m independently represents an
integer from 1-20; R.sub.5 independently represents a hydrogen
radical; a substituted or un-substituted alkyl radical; a
substituted or un-substituted aryl radical; or R.sub.5 and a
neighboring R.sub.5 together represent a link or links comprising a
residue of a crosslinking agent, a substituted or un-substituted
alicyclic radical, a substituted or un-substituted aromatic
radical, or a substituted or un-substituted heterocyclic radical;
or R.sub.5 represents a link with another compound; and b) a
crosslinking agent or residue thereof.
102. The amide polymer according to claim 101, wherein the amide
compound is derived from an organic polyacid selected from the
group consisting of methanetetracarboxylic acid, oxalic acid,
malonic acid, succinic acid, fumaric acid, maleic acid, glutaric
acid, adipic acid, pimelic acid, suberic acid, azelaic acid,
sebacic acid, tartaric acid, glucaric acid, mucic acid, galactaric
acid, xylaric acid, aspartic acid, and 2-amino malonic acid.
103. The amide polymer according to claim 101, wherein the amide
compound is derived from an aldaric acid having the general formula
HOOC--(CHOH).sub.w--COOH wherein w represents an integer from 1 to
20.
104. The amide polymer according to claim 101, wherein the amide
compound is represented by the following Formula III:
##STR00045##
105. The amide polymer according to claim 101, wherein the amide
compound is represented by the following Formula IV:
##STR00046##
106. The amide polymer according to claim 101, wherein the amide
compound is represented by the following Formula V:
##STR00047##
107. The amide polymer according to claim 101, wherein the amide
compound is represented by the following Formula VI: ##STR00048##
Description
FIELD OF THE INVENTION
[0001] This invention relates to amide polymers for binding
compounds or ions, and more specifically relates to
pharmaceutically acceptable compositions, amide dendrimers, amide
polymers or residues thereof for binding target ions.
BACKGROUND OF THE INVENTION
[0002] Hyperphosphatemia frequently accompanies diseases associated
with inadequate renal function such as end stage renal disease
(ESRD), hyperparathyroidism, and certain other medical conditions.
The condition, especially if present over extended periods of time,
leads to severe abnormalities in calcium and phosphorus metabolism
and can be manifested by aberrant calcification in joints, lungs,
and eyes.
[0003] Therapeutic efforts to reduce serum phosphate include
dialysis, reduction in dietary phosphate, and oral administration
of insoluble phosphate binders to reduce gastrointestinal
absorption. Many such treatments have a variety of unwanted side
effects and/or have less than optimal phosphate binding properties,
including potency and efficacy. Accordingly, there is a need for
compositions and treatments with good phosphate-binding properties
and good side effect profiles.
BRIEF SUMMARY OF THE INVENTION
[0004] In one aspect, the present invention relates to amide
compounds, amide polymers and/or compositions comprising or derived
from the same or residues thereof. The amide compounds (amide
dendrimers) comprise amide polyol cores (formed, for example, from
an organic polyacid or ester thereof substituted at one or more of
the acid hydroxyl groups with one or more amine polyols). The amide
compounds can be crosslinked to form amide polymers. Compositions
can comprise one or more amide compounds or residues thereof and/or
amide polymers or residues thereof. Several embodiments of the
invention, including this aspect of the invention, are described in
further detail as follows. Generally, each of these embodiments can
be used in various and specific combinations, and with other
aspects and embodiments for a variety of pharmaceutical and
therapeutic uses unless otherwise stated herein.
[0005] In another aspect, the present invention relates to amine
polyether compounds, amine polyether polymers and/or compositions
comprising or derived from the same or residues thereof. The amine
polyether compounds (amine polyether dendrimers) comprise amine
polyol cores. The amine polyether compounds may be crosslinked to
form amine polyether polymers. Compositions can comprise one or
more amine polyether compounds or residues thereof and/or amine
polyether polymers or residues thereof. Several embodiments of the
invention, including this aspect of the invention, are described in
further detail as follows. Generally, each of these embodiments can
be used in various and specific combinations, and with other
aspects and embodiments for a variety of pharmaceutical and
therapeutic uses unless otherwise stated herein.
[0006] In addition to the amide compounds, amide polymers, amine
polyether compounds and amine polyether polymers of the present
invention as described herein, other forms of the amide compounds,
amide polymers, amine polyether compounds and amine polyether
polymers are within the scope of the invention including
pharmaceutically acceptable salts, solvates, hydrates, prodrugs,
polymorphs, clathrates, and isotopic variants and mixtures thereof
of the amide compounds, amide polymers, amine polyether compounds
and/or amine polyether polymers.
[0007] In addition, amide compounds, amide polymers, amine
polyether compounds and amine polyether polymers of the invention
may have optical centers, chiral centers or double bonds and the
amide compounds, amide polymers, amine polyether compounds and
amine polyether polymers of the present invention include all of
the isomeric forms of these compounds and polymers, including
optically pure forms, racemates, diastereomers, enantiomers,
tautomers and/or mixtures thereof.
[0008] In a first embodiment, the invention is, consists
essentially of, or comprises an amide compound or an amide polymer
that comprises at least one amide compound or residue thereof,
where the amide compound is represented by Formula I, as
follows:
##STR00001##
[0009] wherein n independently represents an integer from 0-20, for
example, 1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R independently
represents a hydrogen radical, a hydroxyl radical, --OR.sub.3,
--R.sub.2OH, --R.sub.2OR.sub.3, or C(O)N(R.sub.1).sub.2; R.sub.1
independently represents a hydrogen radical, a hydroxyl radical,
--OR.sub.3, or a branched or unbranched substituted
C.sub.1-C.sub.10, such as a C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, alkyl
radical, wherein one or more carbon atoms of the alkyl radical may
be partially or fully substituted with --OH and/or --OR.sub.3
groups, for example a C.sub.3-C.sub.8 branched alkyl radical having
more than one substitution, such as C.sub.4-C.sub.7 branched alkyl
substituted with 2 or more --OH and/or --OR.sub.3 groups, or
C.sub.3 branched alkyl substituted with 3 or more --OH and/or
--OR.sub.3 groups; R.sub.2 independently represents a substituted
or unsubstituted, branched or unbranched alkyl radical; and R.sub.3
independently represents the following Formula II:
##STR00002##
[0010] wherein p, q and r independently represent an integer from
0-2, for example, 0, 1 or 2; R.sub.4 independently represents
##STR00003##
[0011] wherein m independently represents an integer from 1-20, for
example, 1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R.sub.5
independently represents a hydrogen radical; a substituted or
un-substituted alkyl radical; a substituted or un-substituted aryl
radical; or R.sub.5 and a neighboring R.sub.5 together represent a
link or links comprising a residue of a crosslinking agent, for
example epichlorohydrin or other crosslinking agents, a substituted
or un-substituted alicyclic radical, a substituted or
un-substituted aromatic radical, or a substituted or un-substituted
heterocyclic radical; or R.sub.5 represents a link with another
compound or a residue thereof.
[0012] In another aspect, the invention provides methods of
treating an animal, including a human. The method generally
involves administering a therapeutically effective amount of an
amide polymer described herein.
[0013] Another aspect of the invention is a pharmaceutical
composition comprising one or more amide polymers or amine
polyether polymers of the present invention with at least one
pharmaceutically acceptable carrier or excipient. The amide
polymers and amine polyether polymers described herein have several
therapeutic applications. For example, they are useful in removing
compounds or ions such as anions, for example
phosphorous-containing compounds or phosphorous containing ions
such as organophosphates and/or phosphates, from the
gastrointestinal tract, such as from the stomach, small intestine
and/or large intestine. In some embodiments, the amide polymers and
amine polyether polymers are used in the treatment of phosphate
imbalance disorders and renal diseases.
[0014] In some embodiments, the invention comprises an amide
polymer or an amine polyether polymer that comprises an amide
dendrimer or residue thereof or an amine polyether dendrimer or
residue thereof, where the dendrimer comprises an amide polyol core
or an amine polyol core and branches emanating from the core, where
the branches are based on substituted or un-substituted .alpha.,
.beta. unsaturated nitrile units. The branches may be formed using
a reiterative reaction sequence that includes a Michael addition of
the substituted or un-substituted .alpha., .beta. unsaturated
nitrile and a reduction of the nitrile group to a primary
amine.
[0015] In yet another aspect, the amide polymers, amine polyether
polymers and/or pharmaceutical compositions are useful for removing
other solutes, such as chloride, bicarbonate, and/or oxalate
containing compounds or ions. Amide polymers and amine polyether
polymers removing oxalate compounds or ions find use in the
treatment of oxalate imbalance disorders. Amide polymers and amine
polyether polymers removing chloride compounds or ions find use in
treating acidosis, for example. In some embodiments, the amide
polymers and amine polyether polymers are useful for removing bile
acids and related compounds.
[0016] The invention further provides compositions containing any
of the above amide polymers or amine polyether polymers where the
amide polymer or amine polyether polymers is in the form of
particles and where the particles are encased in one or more
shells.
[0017] In another aspect, the invention provides pharmaceutical
compositions. In some embodiments, the pharmaceutical composition
contains an amide polymer or an amine polyether polymers of the
invention and a pharmaceutically acceptable excipient. In some
embodiments, the composition is a liquid formulation in which the
amide polymer or the amine polyether polymer is dispersed in a
liquid vehicle, such as water, and suitable excipients. In some
embodiments, the invention provides a pharmaceutical composition
comprising an amide polymer or an amine polyether polymer for
binding a target compound or ion, and one or more suitable
pharmaceutical excipients, where the composition is in the form of
a tablet, sachet, slurry, food formulation, troche, capsule,
elixir, suspension, syrup, wafer, chewing gum or lozenge. In some
embodiments the composition contains a pharmaceutical excipient
selected from the group consisting of sucrose, mannitol, xylitol,
maltodextrin, fructose, sorbitol, and combinations thereof. In some
embodiments the target anion of the amide polymer is an
organophosphate and/or phosphate. In some embodiments the amide
polymer is more than about 50% of the weight of the tablet. In some
embodiments, the tablet is of cylindrical shape with a diameter of
from about 12 mm to about 28 mm and a height of from about 1 mm to
about 8 mm and the amide polymer comprises more than 0.6 to about
2.0 gm of the total weight of the tablet.
[0018] In some of the compositions of the invention, the excipients
are chosen from the group consisting of sweetening agents, binders,
lubricants, and disintegrants. Optionally, the amide polymer is
present as particles of less than about 80 m mean diameter. In some
of these embodiments, the sweetening agent is selected from the
group consisting of sucrose, mannitol, xylitol, maltodextrin,
fructose, and sorbitol, and combinations thereof.
[0019] In some embodiments, the invention provides amide polymers
or compositions that comprise an amide dendrimer or residue
thereof, where the amide dendrimer is formed from a core that
comprises an amide polyol that is substituted with one or more
amine groups represented by the following Formula II:
##STR00004##
[0020] wherein p, q and r independently represent an integer from
0-2, for example, 0, 1 or 2; R.sub.4 independently represents
##STR00005##
[0021] wherein m independently represents an integer from 1-20, for
example, 1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R.sub.5
independently represents a hydrogen radical; a substituted or
un-substituted alkyl radical; a substituted or un-substituted aryl
radical; or R.sub.5 and a neighboring R.sub.5 together represent a
link or links comprising a residue of a crosslinking agent, for
example epichlorohydrin or other crosslinking agents, a substituted
or un-substituted alicyclic radical, a substituted or
un-substituted aromatic radical, or a substituted or un-substituted
heterocyclic radical; or R.sub.5 represents a link with another
compound or a residue thereof.
[0022] In still other embodiments, a polymer network may include
two or more polymers, where at least one of the polymers is an
amide polymer derived from an amide compound represented by Formula
I, that may be linked to form a polymer network. For example, in
some embodiments a polymer network may comprise a residue of two or
more amide polyols, a residue of one or more substituted or
un-substituted .alpha., .beta. unsaturated nitrile groups and a
residue of one or more crosslinking agents. In some embodiments,
the polymer network may be formed where all or substantially all of
the polymers may be amide polymers that are derived from amide
compounds represented by Formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0023] In one aspect, the present invention provides amide
compounds, amide polymers, compositions and methods of using amide
polymers or compositions comprising an amide polymer or amide
compound or residue thereof, where the amide compound is
represented by Formula I. In some embodiments, the compositions may
comprise amide polymers that may be derived from two or more of the
amide compounds described herein.
[0024] In addition, some embodiments may include multiple amide
compounds or residues thereof or amine polyether compounds or
residues thereof that repeat in a copolymer or polymer. Such
polymers may include one or more additional compounds that may be
included in a polymer backbone or as pendant groups either
individually or as repeating groups, and that may provide
separation between the individual amide polymers or amine polyether
polymers.
[0025] As used herein, unless otherwise stated, the term "derived
from" is understood to mean: produced or obtained from another
substance by chemical reaction, especially directly derived from
the reactants, for example an amide compound may be derived from
the reaction of an amide polyol and a substituted or un-substituted
.alpha., .beta. unsaturated nitrile that is subsequently
hydrogenated to form an amide compound having one or more
generations of dendritic branching. Additionally, an amide compound
that is reacted with a linking agent, such as a crosslinking agent
results in an amide polymer that is derived from the amide compound
and the linking agent.
[0026] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula I, as
follows:
##STR00006##
wherein n independently represents an integer from 0-20, for
example, 1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R independently
represents a hydrogen radical, a hydroxyl radical, --OR.sub.3,
--R.sub.2OH, --R.sub.2OR.sub.3, or C(O)N(R.sub.1).sub.2; R.sub.1
independently represents a hydrogen radical, a hydroxyl radical,
--OR.sub.3, or a branched or unbranched substituted
C.sub.1-C.sub.10, such as a C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, alkyl
radical, wherein one or more carbon atoms of the alkyl radical may
be partially or fully substituted with --OH and/or --OR.sub.3
groups, for example a C.sub.3-C.sub.8 branched alkyl radical having
more than one substitution, such as C.sub.4-C.sub.7 branched alkyl
substituted with 2 or more --OH and/or --OR.sub.3 groups, or
C.sub.3 branched alkyl substituted with 3 or more --OH and/or
--OR.sub.3 groups; R.sub.2 independently represents a substituted
or unsubstituted, branched or unbranched alkyl radical; and R.sub.3
is independently represented by the following Formula II:
##STR00007##
wherein p, q and r independently represent an integer from 0-2,
such as 0, 1 or 2; R.sub.4 independently represents
##STR00008##
wherein m independently represents an integer from 1-20, for
example, 1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R.sub.5
independently represents a hydrogen radical; a substituted or
un-substituted alkyl radical; a substituted or un-substituted aryl
radical; or R.sub.5 and a neighboring R.sub.5 together represent a
link or links comprising a residue of a crosslinking agent, for
example epichlorohydrin or other crosslinking agents, a substituted
or un-substituted alicyclic radical, a substituted or
un-substituted aromatic radical, or a substituted or un-substituted
heterocyclic radical; or R.sub.5 represents a link with another
compound or a residue thereof.
[0027] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula I, wherein
R.sub.1 independently represents a branched or unbranched
substituted C.sub.1-C.sub.10 alkyl radical that is partially or
fully substituted with 1-20, for example 2-10, 2-6, 2-4, such as 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or
20, --OH and/or OR.sub.3 groups.
[0028] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula I, wherein at
least one R comprises --OR.sub.3.
[0029] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula I, and where
R.sub.3 independently represents a group represented by the
following Formula IIa:
##STR00009##
[0030] where p, r, R.sub.4 and R.sub.5 are as defined above.
[0031] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula I, where R.sub.3
independently represents a group represented by the following
Formula IIb:
##STR00010##
[0032] where R.sub.4 and R.sub.5 are as defined above.
[0033] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula III, as
follows:
##STR00011##
[0034] where R.sub.3 independently represents a group represented
by Formula II, Formula IIa, or Formula IIb as defined above.
[0035] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula IV, as
follows:
##STR00012##
[0036] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula V, as
follows:
##STR00013##
[0037] wherein R.sub.3 independently represents a group represented
by Formula II, Formula IIa, or Formula IIb as defined above.
[0038] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula VI, as
follows:
##STR00014##
[0039] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide polymer comprises at least one amide compound or
residue thereof, where the amide compound comprises a substituted
amide polyol or residue thereof. The amide polyol may comprise a
residue of a substituted or unsubstituted organic polyacid or ester
thereof and a residue of a substituted or unsubstituted amine
polyol. The amide polyol may be substituted with one or more groups
represented by Formula II, Formula IIa, or Formula IIb as defined
above.
[0040] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide polymer comprises at least one amide compound or
residue thereof, where the amide compound comprises an amide
dendrimer or residue thereof, the amide dendrimer comprising a
substituted amide polyol or residue thereof and a residue or one or
more substituted or unsubstituted .alpha., .beta. unsaturated
nitriles or residues thereof. In some embodiments, the amide polyol
may comprise a residue of a substituted or unsubstituted organic
polyacid or ester thereof and a residue of a substituted or
unsubstituted amine polyol.
[0041] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound comprises a substituted amide polyol
having one or more units, for example 2-40 units, such as 3-30,
4-25, 5-20, 6-15 or 8-12 units or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39 units represented by
the group comprising the following Formula VII:
##STR00015##
[0042] wherein p, q and r independently represent an integer from
0-2, for example, 0, 1 or 2; R.sub.4 independently represents
##STR00016##
[0043] wherein m independently represents an integer from 1-20, for
example, 1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R.sub.5
independently represents a hydrogen radical; a substituted or
un-substituted alkyl radical; a substituted or un-substituted aryl
radical; or R.sub.5 and a neighboring R.sub.5 together represent a
link or links comprising a residue of a crosslinking agent, for
example epichlorohydrin or other crosslinking agents, a substituted
or un-substituted alicyclic radical, a substituted or
un-substituted aromatic radical, or a substituted or un-substituted
heterocyclic radical; or R.sub.5 represents a link with another
compound or a residue thereof.
[0044] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide polymer comprises an amide dendrimer or residue
thereof, the dendrimer comprising a core that is a residue of one
or more substituted or un-substituted organic polyacids or esters
thereof and a residue of one or more amine polyols and the
dendrimer further comprising a residue of one or more substituted
or un-substituted .alpha., .beta. unsaturated nitriles.
[0045] In some embodiments, dendrimers of the present invention may
be formed from any suitable reaction scheme. Dendrimers are
macromolecular compounds that comprise a core that includes
functional groups and dendritic branches that may be formed through
a series of iterative reaction sequences starting with the
functional groups on the core to form a branched macromolecule. In
some embodiments the reactive functional groups comprise hydroxyl
groups and/or amine groups. The functional groups will have
functionalities that are dependent on the type of group. For
example, hydroxyl groups have a functionality of one, while primary
amines generally have a functionality of 2, though they may be
quaternized. In some embodiments, an amide polymer comprises a
dendrimer or residue thereof. In some embodiments, the dendrimer
may comprise an amide polyol core that is a residue of one or more
organic polyacids or esters thereof and a residue of one or more
amine polyols, with the dendrimer further comprising a residue of
one or more substituted or un-substituted .alpha., .beta.
unsaturated nitriles. The amide polymer may further comprise a
crosslinking or other linking agent or residue thereof. Some
examples of substituted or un-substituted .alpha., .beta.
unsaturated nitriles include methacrylonitrile and
acrylonitrile.
[0046] In some embodiments, amide dendrimers of the present
invention are prepared by reaction of an amide polyol core that is
reacted with substituted or un-substituted .alpha., .beta.
unsaturated nitriles and subsequently reduced, resulting in
dendritic branching. An amide polyol core may be formed by reaction
of an amine polyol with an organic polyacid or ester thereof to
form the amide polyol. An example of an amide polyol formed by this
reaction is set forth in Scheme IA, using tartaric acid as the
polyacid and 2-aminopropane-1,2,3-triol as the polyol:
##STR00017##
[0047] The amide polyol may then be reacted by Michael addition of
a substituted or un-substituted .alpha., .beta. unsaturated nitrile
to one or more of the hydroxyl groups on the amide polyol core to
replace the hydrogen of one or more hydroxyl groups with one or
more alkyl cyanide groups, resulting in an ether linkage to the
core via the oxygen atom of the hydroxyl groups. The nitriles of
the alkyl cyanide groups of the resulting compound are then
chemically reduced, for example via hydrogenation, to form the
corresponding primary amines. The Michael addition and subsequent
reduction may be performed on the primary amines yielding branched
tertiary or secondary amines terminating in primary amines.
Subsequent Michael additions and reductions may be repeated one or
more times to provide the branched structure characteristic of
dendrimers. A schematic of this process is provided below in Scheme
IB, using the amide polyol from Scheme IA as the polyol and
acrylonitrile as the .alpha., .beta. unsaturated nitrile:
##STR00018## ##STR00019##
[0048] In some embodiments, each iteration of Michael addition and
subsequent reduction may be considered one generation. Thus, for
some embodiments, a compound having one generation of dendritic
branching may have undergone one iteration of Michael addition and
reduction, compounds having two generations of dendritic branching
may have undergone two iterations of Michael addition and
reduction, compounds having three generations of dendritic
branching may have undergone three iterations of Michael addition
and reduction, compounds having four generations of dendritic
branching may have undergone four iterations of Michael addition
and reduction, etc. Generally dendrimers according to some
embodiments of the present invention may have from 1-10, such as 2,
3, 4, 5, 6, 7, 8, or 9 generations of dendritic branching.
[0049] In some embodiments, a method of making an amide polymer
comprises reacting an organic polyacid or an ester thereof with an
amine polyol to form an amide polyol core, reacting the amide
polyol core with a substituted or un-substituted .alpha., .beta.
unsaturated nitrile using a Michael addition reaction to form a
polyether, reducing at least one nitrile group on the polyether to
form a primary amine, repeating the Michael addition and reduction
on the at least one primary amine one or more times to form an
amide dendrimer; and crosslinking the amide dendrimer with a
crosslinking agent to form an amide polymer.
[0050] In some embodiments, the present invention is a polymer
network, a pharmaceutical composition (comprising or derived from
polymer network or a residue thereof) or a method of using the same
in a therapeutically effective amount to remove a compound or ion,
such as a phosphorous-containing compound or a
phosphorous-containing ion (e.g. phosphate), from the
gastrointestinal tract of an animal where the a polymer network
comprises two or more amide polymers or residues thereof. The
polymer network may comprise a residue of two or more substituted
or un-substituted amide polyols, a residue of one or more
substituted or un-substituted .alpha., .beta. unsaturated nitrile
groups and a residue of one or more crosslinking or other linking
agents. In some embodiments, the polymer network comprises residues
of two or more polyethers, where the polyethers comprise a residue
of one or more amide polyols and a residue of one or more
substituted or un-substituted .alpha., .beta. unsaturated nitrile
groups, and where the network also comprises a residue of one or
more crosslinking agents. In some embodiments, the polymer network
may include one or more amide dendrimers or residues thereof.
[0051] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide polymer comprises two or more amide dendrimers or
residues thereof represented by Formula V, wherein R.sub.3
independently represents a group represented by Formula II, Formula
IIa, or Formula IIb as defined above.
[0052] In some embodiments, the present invention is an amide
polymer (comprising or derived from an amide compound or a residue
thereof), a pharmaceutical composition (comprising or derived from
said amide polymer or a residue thereof), a polymer network
(comprising or derived from said amide polymer or a residue
thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal, the
amide polymer, polymer network or composition having a plurality of
units represented by the following Formula VIII:
##STR00020##
[0053] wherein R.sub.4 independently represents
##STR00021##
[0054] wherein m independently represents an integer from 1-20, for
example, 1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; R.sub.5
independently represents a hydrogen radical; a substituted or
un-substituted alkyl radical; a substituted or un-substituted aryl
radical; or R.sub.5 and a neighboring R.sub.5 together represent a
link or links comprising a residue of a crosslinking agent, for
example epichlorohydrin or other crosslinking agents, a substituted
or un-substituted alicyclic radical, a substituted or
un-substituted aromatic radical, or a substituted or un-substituted
heterocyclic radical; or R.sub.5 represents a link with another
compound or a residue thereof;
[0055] and a plurality of units represented by the following
Formula IX:
##STR00022##
[0056] In some embodiments, the invention is a method for reducing
blood phosphate levels by 5-100% in a patient in need thereof, the
method comprising administering a therapeutically effective amount
of an amide polymer, amine polyether polymer or composition to the
patient, where the amide polymer or composition comprises an amide
compound or residue thereof, the amide compound represented by
Formula I. In some embodiments, the invention is a method for
reducing urinary phosphorous by 5-100% in a patient in need
thereof, the method comprising administering a therapeutically
effective amount of an amide polymer, amine polyether polymer or
composition to the patient, where the amide polymer or composition
comprises an amide compound or residue thereof, the amide compound
represented by Formula I or a residue thereof.
[0057] In some embodiments, the present invention is an amine
polyether compound, an amine polyether polymer (comprising or
derived from said amine polyether compound or a residue thereof), a
pharmaceutical composition (comprising or derived from said amine
polyether compound or a residue thereof or comprising or derived
from said amine polyether polymer or a residue thereof) or a method
of using the same in a therapeutically effective amount to remove a
compound or ion, such as a phosphorous-containing compound or a
phosphorous-containing ion (e.g. phosphate), from the
gastrointestinal tract of an animal where the amine polyether
compound is represented by Formula X, as follows:
##STR00023##
wherein R.sub.8 independently represents a hydrogen radical or
--OR.sub.9 and R.sub.9 independently represents a hydrogen radical
or a group represented by Formula II, Formula IIa or Formula IIb as
defined above.
[0058] In some embodiments, amine polyol compounds that may be used
to form the amide polyol cores for, or in the preparation of amide
compounds, amide polymers, polymer networks and compositions
according to some embodiments of the invention include any amine
polyols and in some embodiments may be represented by the following
general molecular formula:
N.sub.aR.sub.6(OH).sub.c
[0059] where a independently represents an integer from 1 to 6, for
example 1, 2, 3, 4, 5 or 6; c independently represents an integer
from 1-10, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and R.sub.6
independently represents a branched or unbranched, substituted or
unsubstituted C.sub.1 to C.sub.10 alkyl group.
[0060] In some embodiments, examples of some suitable amine polyols
include amine-substituted polyhydric alcohols. Examples of some
polyhydric alcohols that may be amine substituted to form suitable
amine polyols include 1,4-butanediol, 1,5-pentanediol,
1,6-hexanediol, 1,6-cyclohexanedimethanol,
2-methyl-1,3-propanediol, 2-methyl-2-ethyl-1,3-propanediol,
2-ethyl-2-butyl-1,3-propanediol, neopentyl glycol,
dimethylolpropane, 1,1-dimethylolcyclohexane, glycerol,
trimethylolethane, trimethylolpropane, diglycerol,
ditrimethylolethane, ditrimethylolpropane, pentaerythritol,
dipentaerythritol and sugar alcohols.
[0061] Sugar alcohols that may be amine substituted to form
suitable amine polyols include sugar alcohols derived from aldoses
and ketoses including those derived from monoses, dioses, trioses,
tetroses, pentoses, hexoses, heptoses, octoses and nonoses. The
aldoses and ketoses from which the sugar alcohols are derived may
be fully or partially hydrogenated, and may be substituted,
including replacement of one or more hydroxyl groups on the aldose
or ketose with one or more hydrogen groups to form the
corresponding deoxyaldose or deoxyketose, provided that at least
two alcohol groups remain. Specific examples of aldoses and ketoses
from which suitable sugar alcohols may be derived include:
erythrose, threose, ribose, deoxyribose, arabinose, xylose, lyxose,
allose, altrose, glucose, mannose, gulose, idose, galactose,
talose, ribulose, xylulose, fructose, psicose, tagatose,
mannoheptulose, sedoheptulose, sorbose, pentaerythrose, octolose,
sialose or a partially or fully hydrogenated derivatives thereof,
or a combinations thereof. Non-limiting examples of some suitable
sugar alcohols that may be amine substituted include sorbitol,
mannitol, xylitol, erythritol, galactitol, dulcitol, arabitol,
threitol, arabinitol, ribitol, and rhamnitol.
[0062] In some embodiments, suitable amine polyol compounds that
may be used to form the cores for, or in the preparation of amide
compounds, amide polymers, polymer networks and compositions
according to some embodiments of the invention include:
##STR00024##
[0063] In some embodiments, the invention includes amine polyether
compounds that may be formed from any of the amine polyols
described herein. In some embodiments, the amine polyether
compounds are formed via Michael addition and reduction on the
hydroxyl groups and/or amine groups of the amine polyols similar to
the reaction described above with respect to the amide polyols. The
resulting amine polyether compounds may be crosslinked to form
amine polyether polymers. The amine polyether compounds and amine
polyether polymers may be used in pharmaceutical compositions,
polymer networks and methods of treatment as described herein with
respect to the amide polymers and compositions.
[0064] In some embodiments, organic polyacids and/or esters thereof
may be used to form the cores for, or in the preparation of, amide
compounds, amide polymers, polymer networks and compositions
according to some embodiments of the invention. Esters of all of
the organic polyacids may be used instead of, or in conjunction
with, the organic polyacids, including polyacids that are partially
and fully esterified. Examples of the polyacids include any organic
polyacids, including diacids, triacids, tetracids, pentacids and
hexacids. Examples of some polyacids that may be used include
substituted or un-substituted methanetetracarboxylic acid,
ethane-1,1,2,2-tetracarboxylic acid, oxalic acid, malonic acid,
succinic acid, fumaric acid, maleic acid, glutaric acid, adipic
acid, pimelic acid, suberic acid, azelaic acid, sebacic acid,
tartaric acid, tartronic, 3-hydroxypentanedioc acid,
3,4-hydroxyhexanedioc acid, glucaric acid, mucic acid, galactaric
acid, xylaric acid, aspartic acid, 2-amino malonic acid, citric
acid, ethylenediaminetetraacetic acid. In some embodiments, the
organic polyacids include one or more substitutions, where the
substitutions comprise hydroxyl and/or amine groups.
[0065] In some embodiments, suitable organic polyacids that may be
used to form the cores for, or in the preparation of, amide
compounds, amide polymers, polymer networks and compositions
according to some embodiments of the invention include aldaric
acids having the following general formula:
HOOC--(CHOH).sub.w--COOH
[0066] wherein w represents an integer from 1 to 20, for example,
1-15, 1-2, 3-6, 7-10, 11-15, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. Additional examples of
suitable aldaric acids include diacids formed from any of the sugar
alcohols as mentioned above. In some embodiments, one or more of
the non-acid hydroxyl groups of the aldaric acids may be replaced
with an amine group.
[0067] In some embodiments, suitable organic polyacids may be
cyclic polyacids such as aromatic, alicyclic or heterocyclic
polyacids having a 3, 4, 5 or 6 membered ring or rings that are
partially or fully substituted with carboxylic acid groups. For
example, a 3-membered polyacid ring may have 2, or 3 carboxylic
acid groups, a 6-membered polyacid ring may have 2, 3, 4, 5, or 6
carboxylic acid groups and a naphthalene group may have 2, 3, 4, 5,
6, 7 or 8 carboxylic acid groups. The heterocyclic organic
polyacids may be aromatic or non-aromatic and may have up to four
heteroatoms selected from N, O and S and combinations thereof. The
cyclic polyacids may additionally have non-acid substitutions on
the rings including, for example, --OH groups.
[0068] Examples of some aromatic, alicyclic and heterocyclic groups
that may be substituted with at least 2 carboxylic acids to form
suitable organic polyacids include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, piperidinyl, piperizinyl, thiazolidinyl,
imidazolidinyl, pyranyl, tetrahydrofuranyl, oxanyl, benzyl,
pyridinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrimidinyl,
dioxanyl, quinizolinyl, indolinyl, benzothiazolyl, benzooxazolyl,
pyrazinyl, furanyl, thenyl, naphthalenyl and the like.
[0069] Non-limiting examples of some suitable cyclic polyacids
include: cyclohexane-1,2-dicarboxylic acid,
cyclohexane-1,3-dicarboxylic acid, cyclohexane-1,4-dicarboxylic
acid, cyclohexane-1,2,3-tricarboxylic acid,
cyclohexane-1,2,4-tricarboxylic acid,
cyclohexane-1,3,4-tricarboxylic acid,
cyclohexane-1,3,5-tricarboxylic acid,
cyclohexane-1,2,3,4-tetracarboxylic acid,
cyclohexane-1,3,4,5-tetracarboxylic acid,
cyclohexane-1,2,3,4,5-pentacarboxylic acid,
cyclohexane-1,2,3,4,5,6-hexacarboxylic acid,
cyclopentane-1,2-dicarboxylic acid, cyclopentane-1,3-dicarboxylic
acid, cyclopentane-1,2-dicarboxylic acid,
cyclopentane-1,2,3-tricarboxylic acid,
cyclopentane-1,2,4-tricarboxylic acid,
cyclopentane-1,2,3,4-tetracarboxylic acid,
cyclopentane-1,2,3,4,5-pentacarboxylic acid, phthahlic acid,
isophthalic acid, terephthalic acid, hemimellitic acid, trimellitic
acid, trimesic acid, benzene-1,2,3,4-tetracarboxylic acid,
benzene-1,2,3,5-tetracarboxylic acid, pyromellitic acid,
benzene-1,2,3,4,5-pentacarboxylic acid, mellitic acid, quinolinic
acid, 1H-pyrazole-3,4-dicarboxylic acid,
1H-pyrazole-1,3,4-tricarboxylic acid, pyridine-2,4,5-tricarboxylic
acid.
[0070] Examples of some suitable organic polyacids include:
##STR00025## ##STR00026## ##STR00027##
[0071] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XI, as
follows:
##STR00028##
[0072] wherein R.sub.1 is as defined above for Formula I, and
R.sub.7 independently represents H or a group represented by
Formula II, Formula IIa, or Formula IIb as defined above.
[0073] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XII, as
follows:
##STR00029##
[0074] wherein R and R.sub.1 are as defined above for Formula I,
and R.sub.3 independently represents a group represented by Formula
II, Formula IIa, or Formula IIb as defined above.
[0075] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XIII, as
follows:
##STR00030##
[0076] wherein R and R.sub.1 are as defined above for Formula I,
and R.sub.3 independently represents a group represented by Formula
II, Formula IIa, or Formula IIb as defined above.
[0077] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XIV, as
follows:
##STR00031##
[0078] wherein R and R.sub.1 are as defined above for Formula I,
and R.sub.3 independently represents a group represented by Formula
II, Formula IIa, or Formula IIb as defined above.
[0079] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XV, as
follows:
##STR00032##
[0080] wherein R and R.sub.1 are as defined above for Formula I,
and R.sub.3 independently represents a group represented by Formula
II, Formula IIa, or Formula IIb as defined above.
[0081] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XVI, as
follows:
##STR00033##
[0082] wherein R.sub.1 is as defined above for Formula I, and
R.sub.3 independently represents a group represented by Formula II,
Formula IIa, or Formula IIb as defined above.
[0083] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XVII, as
follows:
##STR00034##
[0084] wherein R and R.sub.1 are as defined above for Formula I,
and R.sub.3 independently represents a group represented by Formula
II, Formula IIa, or Formula IIb as defined above.
[0085] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XVIII, as
follows:
##STR00035##
[0086] wherein R is as defined above for Formula I and R.sub.3
independently represents a group represented by Formula II, Formula
IIa, or Formula IIb as defined above.
[0087] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XIX, as
follows:
##STR00036##
[0088] wherein R.sub.1 is as defined above for Formula I and
R.sub.3 independently represents a group represented by Formula II,
Formula IIa, or Formula IIb as defined above.
[0089] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XX, as
follows:
##STR00037##
[0090] wherein R.sub.3 independently represents a group represented
by Formula II, Formula IIa, or Formula IIb as defined above.
[0091] In some embodiments, the present invention is an amide
compound, an amide polymer (comprising or derived from said amide
compound or a residue thereof), a pharmaceutical composition
(comprising or derived from said amide compound or a residue
thereof or comprising or derived from said amide polymer or a
residue thereof) or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal
where the amide compound is represented by Formula XXI, as
follows:
##STR00038##
[0092] wherein R.sub.3 independently represents a group represented
by Formula II, Formula IIa, or Formula IIb as defined above.
[0093] In some embodiments, the invention is a method of treating a
phosphate imbalance disorder such as hyperphosphatemia comprising
administering a therapeutically effective amount of an amide
polymer or composition to a patient in need thereof. In some
embodiments, the amide polymer or composition comprises an amide
compound or residue thereof according to Formula I.
[0094] In some embodiments, a method of treating a phosphate
imbalance disorder such as hyperphosphatemia comprises
administering a therapeutically effective amount of an amine
polyether polymer, an amide polymer or composition to a patient in
need thereof, where the amine polyether polymer or the amide
polymer or composition comprises an amine polyether compound or
residue thereof or an amide compound or residue thereof represented
by at least one of Formulas III-VI, X-XXI or where the amide
polymer or composition comprises a plurality of units according to
Formula VII, or a plurality of units according to Formulas VIII and
IX.
[0095] In some embodiments, the amide compound is a mixture of more
than one amine polyether compound or amide compound, for example
2-20 such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 amine polyether compounds
or amide compounds represented by Formulas I, III-VI or X-XXI. In
some embodiments, the mixture predominantly comprises an amine
polyether compound or an amide compound represented by one of
Formulas I, III, V or X-XXI where q, r and p are independently 0 or
2. For example, in some embodiments a plurality of the mixture,
such as greater than 30 wt. %, greater than 40 wt. %, greater than
50 wt. %, greater than 60 wt. % or greater than 70 wt. % based on
the total weight of the mixture, comprises an amine polyether
compound or residue thereof or an amide compound or residue thereof
represented by one of Formulas I, III, V or X-XXI where q, r and p
are independently 0 or 2. For example, in some embodiments, the
mixture comprises greater than 30 wt %, greater than 40 wt. %,
greater than 50 wt. %, greater than 60 wt. % or greater than 70 wt.
% of an amide compound or residue thereof represented by Formula IV
or Formula VI.
[0096] In some embodiments, the invention comprises an amine
polyether polymer or an amide polymer, the polymer derived from an
amine polyether compound or an amide compound that is a mixture of
amine polyether compounds or amide compounds, a pharmaceutical
composition comprising such an amine polyether polymer or amide
polymer, or a method of using the same in a therapeutically
effective amount to remove a compound or ion, such as a
phosphorous-containing compound or a phosphorous-containing ion
(e.g. phosphate), from the gastrointestinal tract of an animal.
[0097] Other embodiments of the invention include pendant amide
polymers or pendant amine polyether polymers formed with amide
compounds or residues thereof or amine polyether compounds or
residues thereof as pendant groups on a polymer or polymerized
backbone of a polymer. Such pendant amide polymers and pendant
amine polyether polymers may be formed by adding one or more
polymerizable groups to one or more amide groups on an amide
compound to form an amide monomer or to one or more amine groups on
an amine polyether compound to form an amine polyether monomer and
then subsequently polymerizing the polymerizable group to form a
pendant amide polymer comprising an amide compound or residue
thereof or a pendant amine polyether polymer comprising an amine
polyether compound or residue thereof. A schematic example of such
an addition follows [it should be noted in the following that an
amide compound or amine polyether compound designated as "AC" is
intended to represent an amide compound or residue thereof or an
amine polyether compound or residue thereof, of the invention, with
one of its amine groups depicted for purposes of illustrating how a
polymerizable group may be added to an amide compound or an amine
polyether compound]:
##STR00039##
[0098] Non-limiting examples of other polymerizable groups that may
be used with amide compounds or residues thereof and with amine
polyether compounds or residues thereof according to embodiments of
the invention include:
##STR00040##
[0099] One or more polymerizable groups may be added to each amide
compound or amine polyether compound and thus it is possible to
have mixtures of amide monomers or amine polyether monomers having
various pendant ACs having differing numbers of polymerizable
groups. In addition, the pendant amide polymers and pendant amine
polyether polymers made in this fashion may be modified,
crosslinked, formed into a network or substituted post
polymerization. Such modification may be performed for any number
of reasons, including to improve efficacy, tolerability or reduce
side effects.
[0100] Amide monomers may also be formed by addition of amide
compounds to amine-reactive polymers by reacting one or more amine
groups of the amide monomers with one or more amine-reactive groups
on the amine-reactive polymers. Amine polyether monomers may also
be formed by addition of amine polyether compounds to
amine-reactive polymers by reacting one or more amine groups of the
amine polyether monomers with one or more amine-reactive groups on
the amine-reactive polymers. Examples of some amine reactive
polymers include:
##STR00041##
[0101] The amide compounds, amide monomers, amine polyether
compounds or amine polyether monomers may also serve as
multifunctional monomers to form polymers. For example, when the
amide compounds or the polymers formed from the amide monomers or
the amine polyether compounds or the polymers formed from the amine
polyether monomers are crosslinked, the crosslinking reaction may
be carried out either in solution of bulk (i.e. using the neat
amide and neat crosslinking agents) or in dispersed media. When a
bulk process is used, solvents are selected so that they
co-dissolve the reactants and do not interfere with the
crosslinking reaction. Suitable solvents include water, low boiling
alcohols (methanol, ethanol, butanol), dimethylformamide,
dimethylsulfoxide, acetone, methylethylketone, and the like.
[0102] Other polymerization methods may include a single
polymerization reaction, stepwise addition of individual monomers
via a series of reactions, the stepwise addition of blocks of
monomers, combinations of the foregoing, or any other method of
polymerization, such as, for example, direct or inverse suspension,
condensation, emulsion, precipitation techniques, polymerization in
aerosol or using bulk polymerization/crosslinking methods and size
reduction processes such as extrusion and grinding. Processes can
be carried out as batch, semi-continuous and continuous processes.
For processes in dispersed media, the continuous phase can be
selected from apolar solvents such as toluene, benzene,
hydrocarbon, halogenated solvents, supercritical carbon dioxide,
and the like. With a direct suspension process, water can be used,
although salt brines are also useful to "salt out" the amide and
crosslinking agents in a droplet separate phase.
[0103] Amide compounds, amide monomers, amine polyether compounds
and amine polyether monomers of the invention may be copolymerized
with one or more other monomers or oligomers or other polymerizable
groups, may be crosslinked, may have crosslinking or other linking
agents or monomers within the polymer backbone or as pendant groups
or may be formed or polymerized to form a polymer network or mixed
polymer network comprising: amide compounds or residues thereof,
amide monomers or residues thereof, amine polyether compounds or
residues thereof, amine polyether monomers or residues thereof,
crosslinking agents or residues thereof, or other linking agents or
residues thereof. The network may include multiple connections
between the same or different molecules that may be direct or may
include one or more linking groups such as crosslinking agents or
other linking agents such as monomers or oligomers or residues
thereof.
[0104] Non-limiting examples of comonomers which may be used alone
or in combination include: styrene, substituted styrene, alkyl
acrylate, substituted alkyl acrylate, alkyl methacrylate,
substituted alkyl methacrylate, acrylonitrile, methacrylonitrile,
acrylamide, methacrylamide, N-alkylacrylamide,
N-alkylmethacrylamide, N,N-dialkylacrylamide,
N,N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl
acetate, N-vinyl amide, maleic acid derivatives, vinyl ether,
allyle, methallyl monomers and combinations thereof. Functionalized
versions of these monomers may also be used. Additional specific
monomers or comonomers that may be used in this invention include,
but are not limited to, methyl methacrylate, ethyl methacrylate,
propyl methacrylate (all isomers), butyl methacrylate (all
isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate,
methacrylic acid, benzyl methacrylate, phenyl methacrylate,
methacrylonitrile, .alpha.-methylstyrene, methyl acrylate, ethyl
acrylate, propyl acrylate (all isomers), butyl acrylate (all
isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid,
benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, glycidyl
methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl
methacrylate (all isomers), hydroxybutyl methacrylate (all
isomers), N,N-dimethylaminoethyl methacrylate,
N,N-diethylaminoethyl methacrylate, triethyleneglycol methacrylate,
itaconic anhydride, itaconic acid, glycidyl acrylate,
2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers),
hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethyl
acrylate, N,N-diethylaminoethyl acrylate, triethyleneglycol
acrylate, methacrylamide, N-methylacrylamide,
N,N-dimethylacrylamide, N-tert-butylmethacrylamide,
N--N-butylmethacrylamide, N-methylolmethacrylamide,
N-ethylolmethacrylamide, N-tert-butylacrylamide,
N--N-butylacrylamide, N-methylolacrylamide, N-ethylolacrylamide,
4-acryloylmorpholine, vinyl benzoic acid (all isomers),
diethylaminostyrene (all isomers), .alpha.-methylvinyl benzoic acid
(all isomers), diethylamino .alpha.-methylstyrene (all isomers),
p-vinylbenzene sulfonic acid, p-vinylbenzene sulfonic sodium salt,
trimethoxysilylpropyl methacrylate, triethoxysilylpropyl
methacrylate, tributoxysilylpropyl methacrylate,
dimethoxymethylsilylpropyl methacrylate, diethoxymethylsilylpropyl
methacrylate, dibutoxymethylsilylpropyl methacrylate,
diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl
methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl
methacrylate, diisopropoxysilylpropyl methacrylate,
trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate,
tributoxysilylpropyl acrylate, dimethoxymethylsilylpropyl acrylate,
diethoxymethylsilylpropyl acrylate, dibutoxymethylsilylpropyl
acrylate, diisopropoxymethylsilylpropyl acrylate,
dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate,
dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate,
maleic anhydride, N-phenylmaleimide, N-butylmaleimide,
N-vinylformamide, N-vinyl acetamide, allylamide, methallylamide,
allylalcohol, methyl-vinylether, ethylvinylether, butylvinyltether,
butadiene, isoprene, chloroprene, ethylene, vinyl acetate and
combinations thereof.
[0105] In some embodiments, amide polymers or amine polyether
polymers of the invention are crosslinked using crosslinking
agents, and may not dissolve in solvents, and, at most, swell in
solvents. The swelling ratio may be measured according to the
procedure in the Test Methods section below and is typically in the
range of about 1 to about 20; for example 2 to 10, 2.5 to 8, 3 to 6
such as less than 5, less than 6, or less than 7. In some
embodiments, the amide polymers or amine polyether polymers may
include crosslinking or other linking agents that may result in
amide polymers or amine polyether polymers that do not form gels in
solvents and may be soluble or partially soluble in some
solvents.
[0106] Crosslinking agents are typically compounds having at least
two functional groups that are selected from a halogen group,
carbonyl group, epoxy group, ester group, acid anhydride group,
acid halide group, isocyanate group, vinyl group, and chloroformate
group. The crosslinking agent may be attached to the carbon
backbone or to a nitrogen of an amide compound or residue thereof,
an amide monomer or residue thereof, an amine polyether compound or
residue thereof and/or an amine polyether monomer or residue
thereof.
[0107] Examples of crosslinking agents that are suitable for
synthesis of the polymers or dendrimers of the present invention
include, but are not limited to, one or more multifunctional
crosslinking agents such as: dihaloalkanes, haloalkyloxiranes,
alkyloxirane sulfonates, di(haloalkyl)amides, tri(haloalkyl)amides,
diepoxides, triepoxides, tetraepoxides, bis(halomethyl) benzenes,
tri(halomethyl) benzenes, tetra(halomethyl) benzenes,
epihalohydrins such as epichlorohydrin and epibromohydrin
poly(epichlorohydrin), (iodomethyl)oxirane, glycidyl tosylate,
glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1,2-epoxybutane,
bromo-1,2-epoxybutane, 1,2-dibromoethane, 1,3-dichloropropane,
1,2-dichloroethane, 1-bromo-2-chloroethane, 1,3-dibromopropane,
bis(2-chloroethyl)amide, tris(2-chloroethyl)amide, and
bis(2-chloroethyl)methylamide, 1,3-butadiene diepoxide,
1,5-hexadiene diepoxide, diglycidyl ether, 1,2,7,8-diepoxyoctane,
1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propylene
glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2
ethanedioldiglycidyl ether, glycerol diglycidyl ether,
1,3-diglycidyl glyceryl ether, N,N-diglycidylaniline, neopentyl
glycol diglycidyl ether, diethylene glycol diglycidyl ether,
1,4-bis(glycidyloxy)benzene, resorcinol digylcidyl ether,
1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl
ether, 1,4-cyclohexanedimethanol diglycidyl ether,
1,3-bis-(2,3-epoxypropyloxy)-2-(2,3-dihydroxypropyloxy)propane,
1,2-cyclohexanedicarboxylic acid diglycidyl ester,
2,2'-bis(glycidyloxy)diphenylmethane, bisphenol F diglycidyl ether,
1,4-bis(2',3'-epoxypropyl)perfluoro-n-butane, 2,
6-di(oxiran-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindol-1,3,5-
,7-tetraone, bisphenol A diglycidyl ether, ethyl
5-hydroxy-6,8-di(oxiran-2-ylmethyl)-4-oxo-4h-chromene-2-carboxylate,
bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide,
1,3-bis(3-glycidoxypropyl)tetramethyldisiloxane,
9,9-bis[4-(glycidyloxy)phenyl]fluorine, triepoxyisocyanurate,
glycerol triglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniline,
isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid
(R,R,R)-triglycidyl ester, triglycidyl isocyanurate,
trimethylolpropane triglycidyl ether, glycerol propoxylate
triglycidyl ether, triphenylolmethane triglycidyl ether,
3,7,14-tris[[3-(epoxypropoxy)propyl]dimethylsilyloxy]-1,3,5,7,9,11,14-hep-
tacyclopentyltricyclo[7.3.3.15,11]heptasiloxane,
4,4'-methylenebis(N,N-diglycidylaniline), bis(halomethyl)benzene,
bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluene
diisocyanate, acrylol chloride, methyl acrylate, ethylene
bisacrylamide, pyrometallic dianhydride, succinyl dichloride,
dimethylsuccinate. When the crosslinking agent is an alkylhalide
compound, a base can be used to scavenge the acid formed during the
reaction. Inorganic or organic bases are suitable. NaOH is
preferred. The base to crosslinking agent ratio is preferably
between about 0.5 to about 2.
[0108] In some embodiments, the crosslinking agents may be
introduced into the polymerization reaction in an amount of from
0.5 to 25 wt. % based on the total weight of the amide polymer or
amine polyether polymer, such as from about 2 to about 15 wt. %,
from about 2 to about 12 wt. %, from about 3 to about 10 wt. %, or
from about 3 to about 6 wt. %, such as 2, 3, 4, 5, 6 wt %. The
amount of crosslinking agent necessary may depend on the extent of
branching within the amide compound or amine polyether
compound.
[0109] In some embodiment the molecular weight of the amide
polymers or amine polyether polymers, may be typically at least
about 1000. For example, the molecular weight may be from about
1000 to about 1,000,000, such as about 1000 to about 750,000, about
1000 to about 500,000, about 1000 to about 250,000, about 1000 to
about 100,000 such as less than 750,000, less than 500,000, 250,000
or less than 100,000.
[0110] In some embodiments, the pharmaceutical composition of the
present invention comprises an amide polymer comprising at least
one amide compound or residue thereof, where the amide compound is
represented by Formula III where R.sub.5 independently represents
an H radical or an alkyl radical, q and r are 0 and p is 2, m
independently represents an integer from 3-6, such as 3, 4, 5 or 6;
and 2-6 wt. % crosslinking agent or residue thereof, such as 2 wt.
%, 3 wt. %, 4 wt. %, 5 wt. % or 6 wt. % crosslinking agent, where
the crosslinking agent is epichlorohydrin, poly(epichlorohydrin),
1,2-dibromoethane, tris(2-chloroethyl)amide or 1,4-butanediol
diglycidyl ether. Another pharmaceutical composition embodiment of
the present invention comprises an amide polymer comprising at
least one amide compound or residue thereof, where the amide
compound is represented by Formula III where R.sub.5 independently
represents an H radical or an alkyl radical, q is 0 and r and p
both are 2, m independently represents an integer from 3-6, such as
3, 4, 5 or 6, where the compound is crosslinked with a crosslinking
agent as defined above in this paragraph. A further pharmaceutical
composition embodiment of the present invention comprises an amide
polymer comprising at least one amide compound or residue thereof,
where the amide compound is represented by Formula III where
R.sub.5 independently represents an H radical or an alkyl radical,
q, r and p are each 2, m independently represents an integer from
3-6, such as 3, 4, 5 or 6, where the compound is crosslinked with a
crosslinking agent as defined above in this paragraph.
[0111] In some embodiments, the pharmaceutical composition of the
present invention comprises an amide polymer comprising at least
one amide compound or residue thereof, where the amide compound is
represented by Formula V where R.sub.5 independently represents an
H radical or an alkyl radical, q and r are 0 and p is 2, m
independently represents an integer from 3-6, such as 3, 4, 5 or 6;
and 2-6 wt. % crosslinking agent or residue thereof, such as 2 wt.
%, 3 wt. %, 4 wt. %, 5 wt. % or 6 wt. % crosslinking agent, where
the crosslinking agent is epichlorohydrin, poly(epichlorohydrin),
1,2-dibromoethane, tris(2-chloroethyl)amide or 1,4-butanediol
diglycidyl ether. Another pharmaceutical composition embodiment of
the present invention comprises an amide polymer comprising at
least one amide compound or residue thereof, where the amide
compound is represented by Formula V, where R.sub.5 independently
represents an H radical or an alkyl radical, q is 0 and r and p
both are 2, m independently represents an integer from 3-6, such as
3, 4, 5 or 6, where the compound is crosslinked with a crosslinking
agent as defined above in this paragraph. A further pharmaceutical
composition embodiment of the present invention comprises an amide
polymer comprising at least one amide compound or residue thereof,
where the amide compound is represented by Formula V where R.sub.5
independently represents an H radical or an alkyl radical, q, r and
p are each 2, m independently represents an integer from 3-6, such
as 3, 4, 5 or 6, where the compound is crosslinked with a
crosslinking agent as defined above in this paragraph.
[0112] Another pharmaceutical composition of the present invention
comprises an amide polymer comprising an amide compound or residue
thereof, the amide compound comprising a substituted amide polyol
having one or more units represented by Formula VII where R.sub.5
independently represents an H radical or an alkyl radical, q and r
are 0 and p is 2, m independently represents an integer from 3-6,
such as 3, 4, 5 or 6; and 2-6 wt. % crosslinking agent or residue
thereof, such as 2 wt. %, 3 wt. %, 4 wt. %, 5 wt. % or 6 wt. %
crosslinking agent, where the crosslinking agent is
epichlorohydrin, poly(epichlorohydrin), 1,2-dibromoethane,
tris(2-chloroethyl)amide or 1,4-butanediol diglycidyl ether.
Another pharmaceutical composition embodiment of the present
invention comprises an amide polymer comprising an amide compound
or residue thereof, the amide compound comprising a substituted
amide polyol having one or more units represented by Formula VII
where R.sub.5 independently represents an H radical or an alkyl
radical, q is 0 and r and p both are 2, m independently represents
an integer from 3-6, such as 3, 4, 5 or 6, and crosslinked with a
crosslinking agent as defined above in this paragraph. A further
pharmaceutical composition embodiment of the present invention
comprises an amide polymer comprising an amide compound or residue
thereof, the amide compound comprising a substituted amide polyol
having one or more units represented by Formula VII where R.sub.5
independently represents an H radical or an alkyl radical, q, r and
p are each 2, m independently represents an integer from 3-6, such
as 3, 4, 5 or 6, and crosslinked with a crosslinking agent as
defined above in this paragraph.
[0113] In some embodiments, the pharmaceutical composition of the
present invention comprises an amine polyether polymer comprising
at least one amine polyether compound or residue thereof, where the
amine polyether compound is represented by Formula X where R.sub.5
independently represents an H radical or an alkyl radical, q and r
are 0 and p is 2, m independently represents an integer from 3-6,
such as 3, 4, 5 or 6; and 2-6 wt. % crosslinking agent or residue
thereof, such as 2 wt. %, 3 wt. %, 4 wt. %, 5 wt. % or 6 wt. %
crosslinking agent, where the crosslinking agent is
epichlorohydrin, poly(epichlorohydrin), 1,2-dibromoethane,
tris(2-chloroethyl)amide or 1,4-butanediol diglycidyl ether.
Another pharmaceutical composition embodiment of the present
invention comprises an amine polyether polymer comprising at least
one amine polyether compound or residue thereof, where the amine
polyether compound is represented by Formula X where R.sub.5
independently represents an H radical or an alkyl radical, q is 0
and r and p both are 2, m independently represents an integer from
3-6, such as 3, 4, 5 or 6, where the compound is crosslinked with a
crosslinking agent as defined above in this paragraph. A further
pharmaceutical composition embodiment of the present invention
comprises an amine polyether polymer comprising at least one amine
polyether compound or residue thereof, where the amine polyether
compound is represented by Formula X where R.sub.5 independently
represents an H radical or an alkyl radical, q, r and p are each 2,
m independently represents an integer from 3-6, such as 3, 4, 5 or
6, where the compound is crosslinked with a crosslinking agent as
defined above in this paragraph.
[0114] In some embodiments, the invention is a compound or
composition or method for removing an anion, such as
organophosphate or phosphate, from the gastrointestinal tract of an
animal by administering a therapeutically effective amount of an
amide polymer that comprises an amide dendrimer having a core that
is a residue of an amide polyol and a residue of one or more
substituted or un-substituted .alpha., .beta. unsaturated nitriles,
where the amide polyol comprises a residue of an organic polyacid
or ester thereof and a residue of an amine polyol.
[0115] Another pharmaceutical composition of the present invention
comprises an amide polymer that comprises an amide dendrimer or
residue thereof having a core that is a residue of an amide polyol
and a residue of one or more acrylonitriles, where the amide polyol
is a residue of tartaric acid or other aldaric acid or an ester of
tartaric acid or other aldaric acid, and a residue of
tris(hydroxymethyl)aminomethane; where the dendrimer is crosslinked
with 2-6 wt. % crosslinking agent or residue thereof, such as 2 wt.
%, 3 wt. %, 4 wt. %, 5 wt. % or 6 wt. % crosslinking agent, where
the crosslinking agent is epichlorohydrin, poly(epichlorohydrin),
1,2-dibromoethane, tris(2-chloroethyl)amide or 1,4-butanediol
diglycidyl ether. Another pharmaceutical composition embodiment of
the present invention comprises an amide polymer that comprises an
amide dendrimer or residue thereof having a core that is a residue
of an amide polyol and a residue of one or more acrylonitriles,
where the amide polyol is a residue of methantetracarboxylic acid
and tris(hydroxymethyl)aminomethane; and where the dendrimer is
crosslinked with a crosslinking agent as defined above in this
paragraph.
[0116] Another pharmaceutical composition of the present invention
comprises a polymer network having a plurality of units represented
by Formula VIII where n is from 3-6, the composition also having a
plurality of units represented by Formula IX.
[0117] The polymers of some embodiments may be formed using a
polymerization initiator. Generally, any initiator may be used
including cationic and radical initiators. Some examples of
suitable initiators that may be used include: the free radical
peroxy and azo type compounds, such as azodiisobutyronitrile,
azodiisovaleronitrile, dimethylazodiisobutyrate,
2,2'-azobis(isobutyronitrile),
2,2'-azobis(N,N'-dimethyleneisobutyramidine)dihydrochloride,
2,2'-azobis(2-amidinopropane)dihydrochloride,
2,2'-azobis(N,N'-dimethyleneisobutyramidine),
1,1'-azobis(1-cyclohexanecarbo-nitrile),
4,4'-azobis(4-cyanopentanoic acid), 2,2'-azobis(isobutyramide)
dihydrate, 2,2'-azobis(2-methylpropane),
2,2'-azobis(2-methylbutyronitrile), VAZO 67, cyanopentanoic acid,
the peroxy pivalates, dodecylbenzene peroxide, benzoyl peroxide,
di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide,
dicumyl peroxide, cumyl hydroperoxide, dimethyl bis(butylperoxy)
hexane.
[0118] In some embodiments, any of the nitrogen atoms within the
amide compounds or residues thereof or amine polyether compounds or
residues thereof according to embodiments of the invention may
optionally be quaternized to yield the corresponding positively
charged tertiary nitrogen group, such as for example, an ammonium
or substituted ammonium group. Any one or more of the nitrogen
atoms in the amide compound or residue thereof or amine polyether
compound or residue thereof may be quaternized and such
quatemization, when present, is not limited to or required to
include terminal amine nitrogen atoms. In some embodiments, this
quatemization may result in additional network formation and may be
the result of addition of crosslinking, linking or addition of
amine reactive groups to the nitrogen. The ammonium groups may be
associated with a pharmaceutically acceptable counterion.
[0119] In some embodiments, amide compounds, amide polymers, amine
polyether compounds and amine polyether polymers of the invention
may be partially or fully quaternized or partially or fully
protonated, with a pharmaceutically acceptable counterion, which
may be organic ions, inorganic ions, or a combination thereof.
Examples of some suitable inorganic ions include halides (e.g.,
chloride, bromide or iodide) carbonates, bicarbonates, sulfates,
bisulfates, hydroxides, nitrates, persulfates and sulfites.
Examples of some suitable organic ions include acetates,
ascorbates, benzoates, citrates, dihydrogen citrates, hydrogen
citrates, oxalates, succinates, tartrates, taurocholates,
glycocholates, and cholates. Preferred ions include chlorides and
carbonates.
[0120] In some embodiments, amide compounds, amide polymers, amine
polyether compounds and amine polyether polymers of the invention
may be protonated such that the fraction of protonated nitrogen
atoms is from 1 to 25%, preferably 3 to 25%, more preferably 5 to
15%.
[0121] In one embodiment, a pharmaceutically acceptable amide
polymer or amine polyether polymer is an amide polymer or amine
polyether polymer in partially or fully protonated form and
comprises a carbonate anion. In one embodiment the pharmaceutically
acceptable amide polymer or pharmaceutically acceptable amine
polyether polymer is in partially or fully protonated form and
comprises a mixture of carbonate and bicarbonate anions.
[0122] In some embodiments, compounds and polymers of the invention
are characterized by their ability to bind compounds or ions.
Preferably the compounds or polymers of the invention bind anions,
more preferably they bind organophosphates, phosphate and/or
oxalate, and most preferably they bind organophosphates or
phosphate. For illustration, anion-binding amide polymers, anion
binding amine polyether polymers and especially organophosphate or
phosphate-binding amide polymers and organophosphate or
phosphate-binding amine polyether polymers will be described;
however, it is understood that this description applies equally,
with appropriate modifications that will be apparent to those of
skill in the art, to other ions, compounds and solutes. Amide
polymers and amine polyether polymers may bind an ion, e.g., an
anion when they associate with the ion, generally though not
necessarily in a noncovalent manner, with sufficient association
strength that at least a portion of the ion remains bound under the
in vitro or in vivo conditions in which the polymer is used for
sufficient time to effect a removal of the ion from solution or
from the body. A target ion may be an ion to which the amide
polymer or amine polyether polymer binds, and usually refers to the
ion whose binding to the amide polymer or amine polyether polymer
is thought to produce the therapeutic effect of the compound and
may be an anion or a cation. A compound of the invention may have
more than one target ion.
[0123] For example, some of the amide polymers and amine polyether
polymers described herein exhibit organophosphate or phosphate
binding properties. Phosphate binding capacity is a measure of the
amount of phosphate ion a phosphate binder can bind in a given
solution. For example, binding capacities of phosphate binders can
be measured in vitro, e.g., in water or in saline solution, or in
vivo, e.g., from phosphate urinary excretion, or ex vivo, for
example using aspirate liquids, e.g., chyme obtained from lab
animals, patients or volunteers. Measurements can be made in a
solution containing only phosphate ion, or at least no other
competing solutes that compete with phosphate ions for binding to
the amide polymer or amine polyether polymer. In these cases, a non
interfering buffer may be used. Alternatively, measurements can be
made in the presence of other competing solutes, e.g., other ions
or metabolites, that compete with phosphate ions (the target
solute) for binding to the amide polymer or amine polyether
polymer.
[0124] Ion binding capacity for an amide polymer or amine polyether
polymer may be measured as indicated in the Test Methods. Some
embodiments have a phosphate binding capacity which can be greater
than about 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0,
8.0, 10.0, 12, 14, 16, 18 or greater than about 20 mmol/g. In some
embodiments, the in vitro phosphate binding capacity of amide
polymers or amine polyether polymers of the invention for a target
ion is greater than about 0.5 mmol/g, preferably greater than about
2.5 mmol/g, even more preferably greater than about 3 mmol/g, even
more preferably greater than about 4 mmol/g, and yet even more
preferably greater than about 6 mmol/g. In some embodiments, the
phosphate binding capacity can range from about 0.2 mmol/g to about
20 mmol/g, such as about 0.5 mmol/g to about 10 mmol/g, preferably
from about 2.5 mmol/g to about 8 mmol/g, and even more preferably
from about 3 mmol/g to about 6 mmol/g. Phosphate binding may be
measured according to the techniques described in the Test Methods
section below.
[0125] In some embodiments, amide compounds, amide polymers, amine
polyether compounds, amine polyether polymers and compositions of
the invention may reduce urinary phosphorous of a patient in need
thereof by 5-100%, such as 10-75%, 25-65%, or 45-60%. Some
embodiments may reduce urinary phosphorous by greater than 10%,
greater than 20%, greater than 30%, greater than 40%, greater than
45%, greater than 50% or greater than 60%. Reduction of urinary
phosphorous may be measured according to the methods detailed in
the Test Methods section below.
[0126] In some embodiments, amide polymers, amine polyether
polymers and compositions of the invention may reduce blood
phosphate of a patient in need thereof by 5-100%, such as 10-75%,
25-65%, or 45-60%. Some embodiments may reduce blood phosphate
levels by greater than 10%, greater than 20%, greater than 30%,
greater than 40%, greater than 45%, greater than 50% or greater
than 60%.
[0127] When crosslinked, some embodiments of the amide compounds
and amine polyether compounds of the invention form a gel in a
solvent, such as in a simulated gastrointestinal medium or a
physiologically acceptable medium.
[0128] One aspect of the invention is core-shell compositions
comprising a polymeric core and shell. In some embodiments, the
polymeric core comprises the amide polymers or amine polyether
polymers described herein. The shell material can be chemically
anchored to the core material or physically coated. In the former
case, the shell can be grown on the core component through chemical
means, for example by: chemical grafting of shell polymer to the
core using living polymerization from active sites anchored onto
the core polymer; interfacial reaction, i.e., a chemical reaction
located at the core particle surface, such as interfacial
polycondensation; and using block copolymers as suspending agents
during the core particle synthesis.
[0129] In some embodiments, the interfacial reaction and use of
block polymers are the techniques used when chemical methods are
used. In the interfacial reaction pathway, typically, the periphery
of the core particle is chemically modified by reacting small
molecules or macromolecules on the core interface. For example, an
amide containing ion-binding core particle or an amine polyether
containing ion-binding core particle is reacted with a polymer
containing amine reactive groups such as epoxy, isocyanate,
activated esters, halide groups to form a crosslinked shell around
the core.
[0130] In another embodiment, the shell is first prepared using
interfacial polycondensation or solvent coacervation to produce
capsules. The interior of the capsule is then filled up with
core-forming precursors to build the core within the shell
capsule.
[0131] In some embodiments, using the block copolymer approach, an
amphiphilic block copolymer can be used as a suspending agent to
form the core particle in an inverse or direct suspension particle
forming process. When an inverse water-in-oil suspension process is
used, then the block copolymer comprises a first block soluble in
the continuous oil phase and another hydrophilic block contains
functional groups that can react with the core polymer. When added
to the aqueous phase, along with core-forming precursor, and the
oil phase, the block copolymer locates to the water-in-oil
interface and acts as a suspending agent. The hydrophilic block
reacts with the core material, or co-reacts with the core-forming
precursors. After the particles are isolated from the oil phase,
the block copolymers form a thin shell covalently attached to the
core surface. The chemical nature and length of the blocks can be
varied to vary the permeation characteristics of the shell towards
solutes of interest.
[0132] When the shell material is physically adsorbed on the core
material, well known techniques of microencapsulation such as
solvent coacervation, fluidized bed spray coater, or multiemulsion
processes can be used. One method of microencapsulation is the
fluidized bed spray coater in the Wurster configuration. In yet
another embodiment, the shell material is only acting temporarily
by delaying the swelling of the core particle while in the mouth
and esophagus, and optionally disintegrates in the stomach or
duodenum. The shell is then selected in order to hinder the
transport of water into the core particle, by creating a layer of
high hydrophobicity and very low liquid water permeability.
[0133] In one embodiment the shell material carries negative
charges while being in the milieu of use. Not being limited to one
mechanism of action, it is thought that negatively charged shell
material coated on anion-binding beads enhance the binding of small
inorganic ions with a low charge density (such as phosphate) over
competing ions with greater valency or size. Competing anions such
as citrate, bile acids and fatty acids among others, may thus have
a lesser relative affinity to the anion binding core possibly as a
result of their limited permeability across the shell.
[0134] In some embodiments, shell materials are polymers carrying
negative charges in the pH range typically found in the intestine.
Examples include, but are not limited to, polymers that have
pendant acid groups such as carboxylic, sulfonic, hydrosulfonic,
sulfamic, phosphoric, hydrophosphoric, phosphonic, hydrophosphonic,
phosphoramidic, phenolic, boronic and a combination thereof. The
polymer can be protonated or unprotonated; in the latter case the
acidic anion can be neutralized with pharmaceutically acceptable
cations such as Na, K, Li, Ca, Mg, and NH.sub.4.
[0135] In another embodiment the polyanion can be administered as a
precursor that ultimately activates as a polyanion: for instance
certain labile ester or anhydride forms of either polysulfonic or
polycarboxylic acids are prone to hydrolysis in the acidic
environment of the stomach and can convert to the active
anions.
[0136] The shell polymers can be either linear, branched,
hyperbranched, segmented (i.e. backbone polymer arranged in
sequence of contiguous blocks of which at least one contains
pendant acidic groups), comb-shaped, star-shaped or crosslinked in
a network, fully and semi-interpenetrated network (IPN). The shell
polymers are either random or blocky in composition and either
covalently or physically attached to the core material. Examples of
such shell polymers include, but are not limited to acrylic acid
homopolymers or copolymers, methacrylic acid homopolymers or
copolymers, and copolymers of methacrylate and methacrylic acid.
Examples of such polymers are copolymers of methylmethacrylate and
methacrylic acid and copolymers of ethylacrylate and methacrylic
acid, sold under the tradename Eudragit (Rohm GmbH & Co. KG):
examples of which include Eudragit L100-55 and Eudragit L100 (a
methylmethacrylate-methacrylic acid (1:1) copolymer, Degussa/Rohm),
Eudragit L30-D55, Eudragit S 100-55 and Eudragit FS 30D, Eudragit S
100 (a methylmethacrylate-methacrylic acid (2:1) copolymer),
Eudragit LD-55 (an ethylacrylate-methacrylic acid (1:1) copolymer),
copolymers of acrylates and methacrylates with quaternary ammonium
groups, sold under the tradenames Eudragit RL and Eudragit RS, and
a neutral ester dispersion without any functional groups, sold
under the tradename Eudragit NE30-D.
[0137] Additional shell polymers include: poly(styrene sulfonate),
Polycarbophil.RTM.; Polyacrylic acid(s); carboxymethyl cellulose,
cellulose acetate phthalate, hydroxypropyl methylcellulose
phthalate as sold under the tradename HP-50 and HP-55 (Shin-Etsu
Chemical Co., Ltd.), cellulose acetate trimellitate, cellulose
acetate, cellulose acetate butyrate, cellulose acetate propionate,
ethyl cellulose, cellulose derivatives, such as
hydroxypropylmethylcellulose, methylcelluose,
hydroxylethylcellulose, hydroxyethylmethylcellulose,
hydroxylethylethylcelluose and hydroxypropylethylcellulose and
cellulose derivatives such as cellulose ethers useful in film
coating formulations, polyvinyl acetate phthalate, carrageenan,
alginate, or poly(methacrylic acid) esters, acrylic/maleic acid
copolymers, styrene/maleic acid polymers, itaconic acid/acrylic
copolymers, and fumaric/acrylic acid copolymers, polyvinyl acetal
diethylaminoacetate, as sold under the tradename AEA (Sankyo Co.,
Ltd.), methylvinylether/maleic acid copolymers and shellac.
[0138] In some embodiments the shell polymers are selected amongst
pharmaceutically acceptable polymers such as Eudragit L100-55 and
Eudragit L100 (a methylmethacrylate-methacrylic acid (1:1)
copolymer, Degussa/Rohm), Carbopol 934 (polyacrylic acid, Noveon),
C-A-P NF (cellulose acetate phthalate--Eastman), Eastacryl
(methacrylic acid esters--Eastman), Carrageenan and Alginate (FMC
Biopolymer), Anycoat--P (Samsung Fine Chemicals--HPMC Phthalate),
or Aqualon (carboxymethyl cellulose--Hercules),
methylvinylether/maleic acid copolymers (Gantrez), and
styrene/maleic acid (SMA).
[0139] The shell can be coated by a variety of methods. In one
embodiment, the shell materials are added in the drug formulation
step as an active excipient; for example, the shell material can be
included in a solid formulation as a powder, which is physically
blended with the organophosphate or phosphate-binding polymer and
other excipients, optionally granulated, and compressed to form a
tablet. Thus, in some embodiments, the shell material need not
cover the core material in the drug product. For example, the
acidic shell polymer may be added together with the anion binding
core polymer formulated in the shape of a tablet, capsule, gel,
liquid, etc, wafer, extrudates and the shell polymer can then
dissolve and distribute itself uniformly as a shell coating around
the core while the drug product equilibrates in the mouth,
esophagus or ultimately in the site of action, i.e. the GI
tract.
[0140] In some embodiments, the shell is a thin layer of shell
polymer. The layer can be a molecular layer of polyanion on the
core particle surface. The weight to core ratio can be between
about 0.0001% to about 30%, preferably comprised between about
0.01% to about 5%, such as between about 0.1% to about 5%.
[0141] The shell polymers have a minimum molecular weight such that
they do not freely permeate within the core pore volume nor elute
from the core surface. In some embodiments, the molecular weight
(Mw) of the shell acidic polymer is above about 1000 g/mole, such
as above about 5000 g/mole, and or even above about 20,000
g/mole
[0142] The anionic charge density of the shell material (as
prevailing in the milieu of use) is may be between 0.5 mEq/gr to 22
mEq/gr, such as 2 mEq/gr to 15 mEq/gr. If a coating process is used
to form the shell on the polymer particles as part of the
manufacture of the dosage form, then procedures known from those
skilled-in-the-art in the pharmaceutical industry are applicable.
In one embodiment, the shell is formed in a fluidized bed coater
(Wurster coater). In an alternate embodiment, the shell is formed
through controlled precipitation or coascervation, wherein the
polymer particles are suspended in a polymer solution, and the
solvent properties are changed in such a way as to induce the
polymer to precipitate onto or coat the polymer particles.
[0143] Suitable coating processes include the procedures typically
used in the pharmaceutical industry. Typically, selection of the
coating method is dictated by a number of parameters, that include,
but are not limited to the form of the shell material (bulk,
solution, emulsion, suspension, melt) as well as the shape and
nature of the core material (spherical beads, irregular shaped,
etc.), and the amount of shell deposited. In addition, the cores
may be coated with one or more shells and may comprise multiple or
alternating layers of shells.
[0144] The term "phosphate imbalance disorder" as used herein
refers to conditions in which the level of phosphorus present in
the body is abnormal. One example of a phosphate imbalance disorder
includes hyperphosphatemia. The term "hyperphosphatemia" as used
herein refers to a condition in which the element phosphorus is
present in the body at an elevated level. Typically, a patient is
often diagnosed with hyperphosphatemia if the blood phosphate level
is, for example, above about 4.0 or 4.5 milligrams per deciliter of
blood, for example above about 5.0 mg/dl, such as above about 5.5
mg/dl, for example above 6.0 mg/dl, and/or the patient has a
severely impaired glomerular filtration rate such as, for example,
less than about 20% of normal. The present invention may also be
used to treat patients suffering from hyperphosphatemia in End
Stage Renal Disease and who are also receiving dialysis treatment
(e.g., hemodialysis or peritoneal dialysis).
[0145] Other diseases that can be treated with the methods,
compounds, polymers, compositions, and kits of the present
invention include hypocalcemia, hyperparathyroidism, depressed
renal synthesis of calcitriol, tetany due to hypocalcemia, renal
insufficiency, and ectopic calcification in soft tissues including
calcifications in joints, lungs, kidney, conjuctiva, and myocardial
tissues. Also, the present invention can be used to treat Chronic
Kidney Disease (CKD), End Stage Renal Disease (ESRD) and dialysis
patients, including prophylactic treatment of any of the above.
[0146] The amide polymers, amine polyether polymers and
compositions described herein can be used as an adjunct to other
therapies e.g. those employing dietary control of phosphorus
intake, dialysis, inorganic metal salts and/or other polymer
resins.
[0147] The compositions of the present invention are also useful in
removing chloride, bicarbonate, oxalate, and bile acids from the
gastrointestinal tract. Amide polymers and amine polyether polymers
removing oxalate compounds or ions find use in the treatment of
oxalate imbalance disorders, such as oxalosis or hyperoxaluria that
increases the risk of kidney stone formation. Amide polymers and
amine polyether polymers removing chloride compounds or ions find
use in treating acidosis, heartburn, acid reflux disease, sour
stomach or gastritis, for example. In some embodiments, the amide
polymers, amine polyether polymers and compositions of the present
invention are useful for removing fatty acids, bilirubin, and
related compounds. Some embodiments may also bind and remove high
molecular weight molecules like proteins, nucleic acids, vitamins
or cell debris.
[0148] The present invention provides methods, pharmaceutical
compositions, polymers, compounds and kits for the treatment of
animals. The term "animal" or "animal subject" or "patient" as used
herein includes humans as well as other mammals (e.g., in
veterinary treatments, such as in the treatment of dogs or cats, or
livestock animals such as pigs, goats, cows, horses, chickens and
the like). One embodiment of the invention is a method of removing
phosphorous-containing compounds such as organophosphates or
phosphate from the gastrointestinal tract, such as the stomach,
small intestine or large intestine of an animal by administering a
therapeutically effective amount of at least one of the amide
polymers or amine polyether polymers described herein.
[0149] The term "treating" and its grammatical equivalents as used
herein includes achieving a therapeutic benefit and/or a
prophylactic benefit. By therapeutic benefit is meant eradication,
amelioration, or prevention of the underlying disorder being
treated. For example, in a hyperphosphatemia patient, therapeutic
benefit includes eradication or amelioration of the underlying
hyperphosphatemia. Also, a therapeutic benefit is achieved with the
eradication, amelioration, or prevention of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For example, administration of amide polymers or amine
polyether polymers, described herein, to a patient suffering from
renal insufficiency and/or hyperphosphatemia provides therapeutic
benefit not only when the patient's serum phosphate level is
decreased, but also when an improvement is observed in the patient
with respect to other disorders that accompany renal failure and/or
hyperphosphatemia like ectopic calcification and renal
osteodistrophy. For prophylactic benefit, for example, the amide
polymers or amine polyether polymers 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.
[0150] The compositions may also be used to control serum phosphate
in subjects with elevated phosphate levels, for example, by
changing the serum level of phosphate towards a normal or near
normal level, for example, towards a level that is within 10% of
the normal level of a healthy patient.
[0151] Other embodiments of the invention are directed towards
pharmaceutical compositions comprising at least one of the amide
polymers or a pharmaceutically acceptable salt of the amide
polymer, or at least one of the amine polyether polymers or a
pharmaceutically acceptable salt of the amine polyether polymer and
one or more pharmaceutically acceptable excipients, diluents, or
carriers and optionally additional therapeutic agents. The
compounds and polymers may be lyophilized or dried under vacuum or
oven before formulating. The compositions may include a mixture of
one or more compounds or polymers according to the invention and
may be administered to bind one or more target ions.
[0152] The excipients or carriers are "acceptable" in the sense of
being compatible with the other ingredients of the formulation and
not deleterious to the recipient thereof. The formulations can
conveniently be presented in unit dosage form and can be prepared
by any suitable method. The methods typically include the step of
bringing into association the agent with the excipients or carriers
such as by uniformly and intimately bringing into association the
amide polymer or amine polyether polymer with the excipients or
carriers and then, if necessary, dividing the product into unit
dosages thereof.
[0153] The pharmaceutical compositions of the present invention
include compositions wherein the amide compounds, amide polymers,
amine polyether compounds and/or amine polyether polymers are
present in a therapeutically effective amount, i.e., in an amount
effective to achieve therapeutic and/or prophylactic benefit. The
actual amount effective for a particular application will depend on
the patient (e.g. age, weight) the condition being treated; and the
route of administration.
[0154] The dosages of the amide polymers or amine polyether
polymers in animals will depend on the disease being, treated, the
route of administration, and the physical characteristics of the
animal being treated. Such dosage levels in some embodiments for
either therapeutic and/or prophylactic uses may be from about 1
gm/day to about 30 gm/day, for example from about 2 gm/day to about
20 gm/day or from about 3 gm/day to about 7 gm/day. The dose of the
amide polymers or amine polyether polymers described herein can be
less than about 50 gm/day, less than about 40 gm/day, less than
about 30 gm/day, less than about 20 gm/day, and less than about 10
gm/day.
[0155] Typically, the amide polymers or amine polyether polymers
can be administered before or after a meal, or with a meal. As used
herein, "before" or "after" a meal is typically within two hours,
preferably within one hour, more preferably within thirty minutes,
most preferably within ten minutes of commencing or finishing a
meal, respectively.
[0156] Generally, it is preferred that the amide polymers or amine
polyether polymers are administered along with meals. The amide
polymers or amine polyether polymers may be administered one time a
day, two times a day, or three times a day. Preferably the amide
polymers or amine polyether polymers are administered once a day
with the largest meal.
[0157] Preferably, the amide polymers or amine poly ether polymers
may be used for therapeutic and/or prophylactic benefits and can be
administered alone or in the form of a pharmaceutical composition.
The pharmaceutical compositions comprise the amide polymers or
amine polyether polymers, one or more pharmaceutically acceptable
carriers, diluents or excipients, and optionally additional
therapeutic agents. For example, the amide polymers or amine
polyether polymers of the present invention may be co-administered
with other active pharmaceutical agents depending on the condition
being treated. Examples of pharmaceutical agents that may be
co-administered include, but are not limited to:
[0158] Other phosphate sequestrants including pharmaceutically
acceptable lanthanum, calcium, aluminum, magnesium and zinc
compounds, such as acetates, carbonates, oxides, hydroxides,
citrates, alginates, and ketoacids thereof.
[0159] Calcium compounds, including calcium carbonate, acetate
(such as PhosLo.RTM. calcium acetate tablets), citrate, alginate,
and ketoacids, have been utilized for phosphate binding.
[0160] Aluminium-based phosphate sequestrants, such as
Amphojel.RTM. aluminium hydroxide gel, have also been used for
treating hyperphosphatemia. These compounds complex with intestinal
phosphate to form highly insoluble aluminium phosphate; the bound
phosphate is unavailable for absorption by the patient.
[0161] The most commonly used lanthanide compound, lanthanum
carbonate (Fosrenol.RTM.) behaves similarly to calcium
carbonate.
[0162] Other phosphate sequestrants suitable for use in the present
invention include pharmaceutically acceptable magnesium compounds.
Various examples of pharmaceutically acceptable magnesium compounds
are described in U.S. Provisional Application No. 60/734,593 filed
Nov. 8, 2005, the entire teachings of which are incorporated herein
by reference. Specific suitable examples include magnesium oxide,
magnesium hydroxide, magnesium halides (e.g., magnesium fluoride,
magnesium chloride, magnesium bromide and magnesium iodide),
magnesium alkoxides (e.g., magnesium ethoxide and magnesium
isopropoxide), magnesium carbonate, magnesium bicarbonate,
magnesium formate, magnesium acetate, magnesium trisilicates,
magnesium salts of organic acids, such as fumaric acid, maleic
acid, acrylic acid, methacrylic acid, itaconic acid and
styrenesulfonic acid, and a combination thereof.
[0163] Various examples of pharmaceutically acceptable zinc
compounds are described in PCT Application No. PCT/US2005/047582
filed Dec. 29, 2005, the entire teachings of which are incorporated
herein by reference. Specific suitable examples of pharmaceutically
acceptable zinc compounds include zinc acetate, zinc bromide, zinc
caprylate, zinc carbonate, zinc chloride, zinc citrate, zinc
formate, zinc hexafluorosilicate, zinc iodate, zinc iodide, zinc
iodide-starch, zinc lactate, zinc nitrate, zinc oleate, zinc
oxalate, zinc oxide, calamide (zinc oxide with a small proportion
of ferric oxide), zinc p-phenolsulfonate, zinc propionate, zinc
salicylate, zinc silicate, zinc stearate, zinc sulfate, zinc
sulfide, zinc tannate, zinc tartrate, zinc valerate and zinc
ethylenebis(dithiocarbamate). Another example includes poly(zinc
acrylate).
[0164] When referring to any of the above-mentioned phosphate
sequestrants, it is to be understood that mixtures, polymorphs and
solvates thereof are encompassed.
[0165] In some embodiments, a mixture of the phosphate sequestrants
described above can be used in the invention in combination with
pharmaceutically acceptable ferrous iron salts.
[0166] In other embodiments, the phosphate sequestrant used in
combination with compounds of the present invention is not a
pharmaceutically acceptable magnesium compound. In yet other
embodiments, the phosphate sequestrant used in combination with the
pharmaceutically acceptable amide compounds, amide polymers, amine
polyether compounds and/or amine polyether polymers is not a
pharmaceutically acceptable zinc compound.
[0167] The invention also includes methods and pharmaceutical
compositions directed to a combination therapy of the amide
polymers or amine polyether polymers in combination with a
phosphate transport inhibitor or an alkaline phosphatase inhibitor.
Alternatively, a mixture of the amide polymers or amine polyether
polymers is employed together with a phosphate transport inhibitor
or an alkaline phosphatase inhibitor.
[0168] Suitable examples of phosphate transport inhibitors can be
found in co-pending U.S. Application Publication Nos. 2004/0019113
and 2004/0019020 and WO 2004/085448, the entire teachings of each
of which are incorporated herein by reference.
[0169] A large variety of organic and inorganic molecules are
inhibitors to alkaline phosphatase (ALP) (see, for example, U.S.
Pat. No. 5,948,630, the entire teachings of which are incorporated
herein by reference). Examples of alkaline phosphatase inhibitors
include orthophosphate, arsenate, L-phenylalanine, L-homoarginine,
tetramisole, levamisole, L-p-Bromotetramisole,
5,6-Dihydro-6-(2-naphthyl) imidazo-[2,1-b]thiazole (napthyl) and
derivatives thereof. The preferred inhibitors include, but are not
limited to, levamisole, bromotetramisole, and
5,6-Dihydro-6-(2-naphthyl)imidazo-[2,1-b]thiazole and derivatives
thereof.
[0170] This co-administration can include simultaneous
administration of the two agents in the same dosage form,
simultaneous administration in separate dosage forms, and separate
administration. For example, for the treatment of
hyperphosphatemia, the amide polymers or amine polyether polymers
may be co-administered with calcium salts which are used to treat
hypocalcemia resulting from hyperphosphatemia.
[0171] The pharmaceutical compositions of the invention can be
formulated as a tablet, sachet, slurry, food formulation, troche,
capsule, elixir, suspension, syrup, wafer, chewing gum or
lozenge.
[0172] Preferably, the amide polymers, amine polyether polymers or
the pharmaceutical compositions comprising the amide polymers or
amine polyether polymers is administered orally. Illustrative of
suitable methods, vehicles, excipients and carriers are those
described, for example, in Remington's Pharmaceutical Sciences,
19th ed., the contents of which is incorporated herein by
reference.
[0173] Pharmaceutical compositions for use in accordance with the
present invention may be formulated in conventional manner using
one or more physiologically acceptable carriers comprising
excipients and auxiliaries which facilitate processing of the
active compounds into preparations which can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen. Suitable techniques for preparing
pharmaceutical compositions of the amide polymers and amine
polyether polymers are well known in the art.
[0174] In some aspects of the invention, the amide polymer(s) or
amine polyether polymer(s) provide mechanical and thermal
properties that are usually performed by excipients, thus
decreasing the amount of such excipients required for the
formulation. In some embodiments the amide polymer or amine
polyether polymer constitutes over about 30 wt. %, for example over
about 40 wt. %, over about 50 wt. %, preferably over about 60 wt.
%, over about 70 wt. %, more preferably over about 80 wt. %, over
about 85 wt. % or over about 90 wt. % of the composition, the
remainder comprising suitable excipient(s).
[0175] In some embodiments, the compressibility of the tablets is
strongly dependent upon the degree of hydration (moisture content)
of the amide polymer or amine polyether polymer. Preferably, the
amide polymer or amine polyether polymer has a moisture content of
about 5% by weight or greater, more preferably, the moisture
content is from about 5% to about 9% by weight, and most preferably
about 7% by weight. It is to be understood that in embodiments in
which the amide polymer or amine polyether polymer is hydrated, the
water of hydration is considered to be a component of the amide
polymer or amine polyether polymer.
[0176] The tablet can further comprise one or more excipients, such
as hardeners, glidants and lubricants, which are well known in the
art. Suitable excipients include colloidal silicon dioxide, stearic
acid, magnesium silicate, calcium silicate, sucrose, calcium
stearate, glyceryl behenate, magnesium stearate, talc, zinc
stearate and sodium stearylfumarate.
[0177] The tablet core of embodiments of the invention may be
prepared by a method comprising the steps of: (1) hydrating or
drying the amide polymer or amine polyether polymer to the desired
moisture level; (2) blending the amide polymer or amine polyether
polymer with any excipients; and (3) compressing the blend using
conventional tableting technology.
[0178] In some embodiments, the invention relates to a stable,
swallowable coated tablet, particularly a tablet comprising a
hydrophilic core, such as a tablet comprising the amide polymer or
amine polyether polymer, as described above. In one embodiment, the
coating composition comprises a cellulose derivative and a
plasticizing agent. The cellulose derivative is, preferably,
hydroxypropylmethylcellulose (HPMC). The cellulose derivative can
be present as an aqueous solution. Suitable
hydroxypropylmethylcellulose solutions include those containing
HPMC low viscosity and/or HPMC high viscosity. Additional suitable
cellulose derivatives include cellulose ethers useful in film
coating formulations. The plasticizing agent can be, for example,
an acetylated monoglyceride such as diacetylated monoglyceride. The
coating composition can further include a pigment selected to
provide a tablet coating of the desired color. For example, to
produce a white coating, a white pigment can be selected, such as
titanium dioxide.
[0179] In one embodiment, the coated tablet of the invention can be
prepared by a method comprising the step of contacting a tablet
core of the invention, as described above, with a coating solution
comprising a solvent, at least one coating agent dissolved or
suspended in the solvent and, optionally, one or more plasticizing
agents. Preferably, the solvent is an aqueous solvent, such as
water or an aqueous buffer, or a mixed aqueous/organic solvent.
Preferred coating agents include cellulose derivatives, such as
hydroxypropylmethylcellulose. Typically, the tablet core is
contacted with the coating solution until the weight of the tablet
core has increased by an amount ranging from about 4% to about 6%,
indicating the deposition of a suitable coating on the tablet core
to form a coated tablet.
[0180] Other pharmaceutical excipients useful in the some
compositions of the invention include a binder, such as
microcrystalline cellulose, carbopol, providone and xanthan gum; a
flavoring agent, such as mannitol, xylitol, maltodextrin, fructose,
or sorbitol; a lubricant, such as vegetable based fatty acids; and,
optionally, a disintegrant, such as croscarmellose sodium, gellan
gum, low-substituted hydroxypropyl ether of cellulose, sodium
starch glycolate. Such additives and other suitable ingredients are
well-known in the art; see, e.g., Gennaro A R (ed), Remington's
Pharmaceutical Sciences, 19th Edition.
[0181] In some embodiments the amide polymers or amine polyether
polymers of the invention are provided as pharmaceutical
compositions in the form of chewable tablets. In addition to the
active ingredient, the following types of excipients are commonly
used: a sweetening agent to provide the necessary palatability,
plus a binder where the former is inadequate in providing
sufficient tablet hardness; a lubricant to minimize frictional
effects at the die wall and facilitate tablet ejection; and, in
some formulations a small amount of a disintegrant is added to
facilitate mastication. In general excipient levels in
currently-available chewable tablets are on the order of 3-5 fold
of active ingredient(s) whereas sweetening agents make up the bulk
of the inactive ingredients. In some embodiments the invention
provides a pharmaceutical composition formulated as a chewable
tablet, comprising an amide polymer or amine polyether polymer
described herein, a filler, and a lubricant. In some embodiments
the invention provides a pharmaceutical composition formulated as a
chewable tablet, comprising an amide polymer or amine polyether
polymer described herein, a filler, and a lubricant, wherein the
filler is chosen from the group consisting of sucrose, mannitol,
xylitol, maltodextrin, fructose, and sorbitol, and wherein the
lubricant is a magnesium fatty acid salt, such as magnesium
stearate.
[0182] In one embodiment, the amide polymer or amine polyether
polymer is pre-formulated with a high Tg/high melting point low
molecular weight excipient such as mannitol, sorbose, sucrose in
order to form a solid solution wherein the polymer and the
excipient are intimately mixed. Methods of mixing such as
extrusion, spray-drying, chill drying, lyophilization, or wet
granulation are useful. Indication of the level of mixing is given
by known physical methods such as differential scanning calorimetry
or dynamic mechanical analysis.
[0183] In some embodiments the amide polymers or amine polyether
polymers of the invention are provided as pharmaceutical
compositions in the form of liquid formulations. In some
embodiments the pharmaceutical composition contains polymer
dispersed in a suitable liquid excipient. Suitable liquid
excipients are known in the art; see, e.g., Remington's
Pharmaceutical Sciences.
[0184] In some embodiments, the pharmaceutical compositions may be
in the form of a powder formulation packaged as a sachet that may
be mixed with water or other ingestible liquid and administered
orally as a drink (solution or suspension). In order to ensure that
such formulations provide acceptable properties to the patient such
as mouth feel and taste, a pharmaceutically acceptable anionic
stabilizer may be included in the formulation.
[0185] Examples of suitable anionic stabilizers include anionic
polymers such as: an anionic polypeptide, an anionic
polysaccharide, or a polymer of one or more anionic monomers such
as polymers of mannuronic acid, guluronic acid, acrylic acid,
methacrylic acid, glucuronic acid glutamic acid or a combination
thereof, and pharmaceutically acceptable salts thereof. Other
examples of anionic polymers include cellulose, such as
carboxyalkyl cellulose or a pharmaceutically acceptable salt
thereof. The anionic polymer may be a homopoloymer or copolymer of
two or more of the anionic monomers described above. Alternatively,
the anionic copolymer may include one or more anionic monomers and
one or more neutral comonomers such as olefinic anionic monomers
such as vinyl alcohol, acrylamide, and vinyl formamide.
[0186] Examples of anionic polymers include alginates (e.g. sodium
alginate, potassium alginate, calcium alginate, magnesium alginate,
ammonium alginate, and esters of alginate), carboxymethyl
cellulose, polylactic acid, polyglutamic acid, pectin, xanthan,
carrageenan, furcellaran, gum Arabic, karaya gum, gum ghatti, gum
carob, and gum tragacanth. Preferred anionic polymers are alginates
and are preferably esterified alginates such as a C2-C5-diol ester
of alginate or a C3-C8 triol ester of alginate. As used herein an
"esterified alginate" means an alginic acid in which one or more of
the carboxyl groups have of the alginic acid are esterified. The
remainder of the carboxylic acid groups in the alginate are
optionally neutralized (partially or completely) as
pharmaceutically acceptable salts. For example, propylene glycol
alginate is an ester of alginic acid in which some of the carboxyl
groups are esterified with propylene glycol, and the remainder of
the carboxylic acid groups are optionally neutralized with
pharmaceutically acceptable salts. More preferably, the anionic
polymer is ethylene glycol alginate, propylene glycol alginate or
glycerol alginate, with propylene glycol alginate even more
preferred.
[0187] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
[0188] It will be apparent to one of ordinary skill in the art that
many changes and modification can be made to the disclosures
presented herein without departing from the spirit or scope of the
appended claims.
EXAMPLES
Example 1 Synthesis of an Amide Polyol
[0189] To a three-necked flask equipped with a magnetic stir bar
was added 9 g of dimethyl L-tartarate, 12.85 g of
tris(hydroxymethyl)aminomethane and 28 ml of methanol and the
resulting solution was stirred at 50.degree. C. for 20 hours. The
addition of heat was stopped, and the solution was self-cooled to
42.degree. C. and then filtered and dried at 30.degree. C. in a
vacuum oven for 20 hours to give 11.3 g of a white solid.
Test Methods
Amide Polymer/Amine Polyether Polymer Urinary Phosphorous Reduction
(In Vivo-Rats)
[0190] House male Sprague Dawley (SD) rats are used for the
experiments. The rats are placed singly in wire-bottom cages, fed
with Purina 5002 diet, and allowed to acclimate for at least 5 days
prior to experimental use.
[0191] To establish baseline phosphorus excretion, the rats are
placed in metabolic cages for 48 hours. Their urine is collected
and its phosphorus content analyzed with a Hitachi analyzer to
determine phosphorus excretion in mg/day. Any rats with outlying
values are excluded; and the remainder of the rats are distributed
into groups.
[0192] Purina 5002 is used as the standard diet. The amide polymer
or amine polyether polymer being tested is mixed with Purina 5002
to result in a final concentration 0.25%, 0.35%, 0.5% and 1% by
weight of the feed. Cellulose at 0.5% by weight is used as a
negative control. Sevelamer is used as a positive control. In the
event that a high-fat diet is used, rats are given feed comprising
Purina 5002, 0.25%, 0.35%, 0.5% and 1% by weight of the feed of the
polymer and 10% by weight of the feed of purified Olive oil, with
the purified olive oil commercially available from Sigma. For each
rat, 200 g of diet is prepared.
[0193] Each rat is weighed and placed on the standard diet. After 4
days the standard diet is replaced with the treatment or high fat
diet, (or control diet for the control group). On days 5 and 6,
urine samples from the rats at 24 hours (+/-30 minutes) is
collected and analyzed. The test rats are again weighed, and any
weight loss or gain is calculated. Any remaining food is also
weighed to calculate the amount of food consumed per day. A change
in phosphorus excretion relative to baseline and cellulose negative
control may be calculated. Percentage reduction of urinary
phosphorous is determined by the following equation:
% Reduction of Urinary Phosphorous=[(urinary phosphorous of
negative control (mg/day)-urinary phosphorous of
experimental(mg/day))/urinary phosphorous of negative
control(mg/day)].times.100.
In Vitro Phosphate Binding (mmol/g)
[0194] Two samples per polymer are weighed into plastic bottles
after having adjusted the weight of the polymer for the loss on
drying of each sample. A 10 mM phosphate buffer solution containing
10 mM KH.sub.2PO.sub.4, 100 mM
N,N-bis[2-hydroxyethyl]-2-aminoethanesulfonic acid, 80 mM NaCl, 15
mM glycochenodeoxycholic acid (GCDC), and 15 mM oleic acid (pH
adjusted to 7.0 with 1 N NaOH) is prepared and well mixed. Aliquots
of the 10 mM phosphate buffer solution is transferred into each of
the two sample bottles. The solutions are well mixed and then
placed into an orbital shaker at 37.degree. C. for 1 hour. The
polymer is allowed to settle prior to removing a sample aliquot
from each solution. The sample aliquot is filtered into a small
vial using a disposable syringe and syringe filter. The filtered
sample is diluted 1-to-10 with DI water. The shaking is continued
for a further 4 hours (total of 5 hours) and the sampling procedure
is repeated. Phosphate standards are prepared from a 10 mM
phosphate standard stock solution and diluted appropriately to
provide standards in the range of 0.3 to 1.0 mM. Both the standards
and samples are analyzed by ion chromatography. A standard curve is
set up and the unbound phosphate (mM) for each test solution is
calculated. Bound phosphate is determined by the following
equation:
Bound Phosphate(mmol/g)=[(10-Unbound
PO.sub.4).times.Vol..times.1000]/MassP; wherein Vol.=volume of test
solution(L); MassP=LOD adjusted mass of polymer (mg).
In-Process Swelling Ratio (mL/g)
[0195] The in-process swelling ratio (SR) is determined by the
following equation:
SR=(weight of wet gel (g)-weight of dry polymer (g))/weight of dry
polymer (g).
[0196] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
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