U.S. patent application number 16/352455 was filed with the patent office on 2019-09-05 for pharmaceutical-grade ferric organic compounds, uses thereof and methods of making same.
The applicant listed for this patent is Panion & BF Biotech Inc.. Invention is credited to Keith CHAN, David W.K. Kwok, Nikolay Mintchev Stoynov, Winston Town.
Application Number | 20190269722 16/352455 |
Document ID | / |
Family ID | 67767892 |
Filed Date | 2019-09-05 |
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United States Patent
Application |
20190269722 |
Kind Code |
A1 |
CHAN; Keith ; et
al. |
September 5, 2019 |
PHARMACEUTICAL-GRADE FERRIC ORGANIC COMPOUNDS, USES THEREOF AND
METHODS OF MAKING SAME
Abstract
The present invention discloses pharmaceutical-grade ferric
organic compounds, including ferric citrate, which are soluble over
a wider range of pH, and which have a large active surface area. A
manufacturing and quality control process for making a
pharmaceutical-grade ferric citrate that consistently complies with
the established Manufacture Release Specification is also
disclosed. The pharmaceutical-grade ferric organic compounds are
suitable for treating disorders characterized by elevated serum
phosphate levels.
Inventors: |
CHAN; Keith; (Rockville,
MD) ; Town; Winston; (Hong Kong, CN) ; Kwok;
David W.K.; (Vancouver, CA) ; Stoynov; Nikolay
Mintchev; (Vancouver, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Panion & BF Biotech Inc. |
Taipei |
|
TW |
|
|
Family ID: |
67767892 |
Appl. No.: |
16/352455 |
Filed: |
March 13, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15699025 |
Sep 8, 2017 |
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16352455 |
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14701933 |
May 1, 2015 |
9757416 |
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15699025 |
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14306756 |
Jun 17, 2014 |
9050316 |
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14701933 |
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13661558 |
Oct 26, 2012 |
8754257 |
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14306756 |
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13289048 |
Nov 4, 2011 |
8299298 |
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13661558 |
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12064058 |
Feb 18, 2008 |
8093423 |
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PCT/US2006/032385 |
Aug 18, 2006 |
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13289048 |
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11206981 |
Aug 18, 2005 |
7767851 |
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12064058 |
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PCT/US2004/004646 |
Feb 18, 2004 |
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11206981 |
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60709511 |
Aug 19, 2005 |
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60462684 |
Apr 15, 2003 |
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60447690 |
Feb 19, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 51/412 20130101;
C07C 51/418 20130101; C07C 59/265 20130101; A61K 31/295 20130101;
A61K 33/26 20130101 |
International
Class: |
A61K 33/26 20060101
A61K033/26; C07C 59/265 20060101 C07C059/265; A61K 31/295 20060101
A61K031/295; C07C 51/41 20060101 C07C051/41 |
Claims
1-57. (canceled)
58. A method of treating hyperphosphatemia, comprising
administering one or more tablets comprising ferric citrate and a
pharmaceutically acceptable carrier to an adult subject, wherein:
(a) the subject has chronic kidney disease and is undergoing
dialysis, (b) the tablets are prepared from a form of ferric
citrate having a BET active surface area of at least about 16
m.sup.2/g, and (c) the tablets are administered to provide a dose
between 4 and 15 grams of ferric citrate to the subject per
day.
59. The method of claim 58, wherein the chronic kidney disease is
selected from mid-stage kidney disease and late-stage kidney
disease.
60. The method of claim 58, wherein the dialysis is selected from
hemodialysis and peritoneal dialysis.
61. The method of claim 58, wherein the tablets are administered to
provide a dose of 6 to 12 grams of the ferric citrate to the
subject per day.
62. The method of claim 58, wherein the tablets are administered to
provide a dose of 6 grams of the ferric citrate to the subject per
day.
63. The method of claim 58, wherein the tablets are administered
twice, or three times per day.
64. The method of claim 58, wherein the dose of the ferric citrate
is adjusted based on serum phosphorus levels of the subject.
Description
[0001] This application is a Continuation of U.S. Ser. No.
14/306,756, filed Jun. 17, 2014, which is a Continuation of U.S.
Ser. No. 13/661,558, filed Oct. 26, 2012, which is a Continuation
of U.S. Ser. No. 13/289,048, filed Nov. 4, 2011, which is a
Continuation of U.S. Ser. No. 12/064,058, filed Feb. 18, 2008,
which is a National Stage of International Application No.
PCT/US2006/032385, filed Aug. 18, 2006, which claims the benefit of
U.S. Ser. No. 60/709,511, filed Aug. 19, 2005, and is a
Continuation-in-part of U.S. Ser. No. 11/206,981, filed Aug. 18,
2005, which is a Continuation-in-part of Int'l App'l No.
PCT/US2004/004646, filed Feb. 18, 2004, which claims the benefit of
U.S. Ser. No. 60/462,684, filed Apr. 15, 2003, and U.S. Ser. No.
60/447,690, filed Feb. 19, 2003. The entire contents and
disclosures of the preceding applications are incorporated herein
by reference into this application.
[0002] Throughout this application, various publications are
referenced. Disclosures of these publications in their entireties
are hereby incorporated by reference into this application to more
fully describe the state of the art to which this invention
pertains.
TECHNICAL FIELD
[0003] This invention relates to the preparation and use of
pharmaceutical-grade ferric organic compounds, such as ferric
citrate. Uses of the pharmaceutical-grade ferric citrate described
herein, include, but are not limited to methods of treating various
disorders in humans and non-human subjects or patients.
BACKGROUND OF THE INVENTION
Uses of Iron Compounds
[0004] Ferric iron containing compounds are useful in the treatment
of a number of disorders, including, but not limited to,
hyperphosphatemia and metabolic acidosis. See Hsu et al., "New
Phosphate Binding Agents: Ferric Compounds", J Am Soc Nephrol, Vol.
10, Pages 1274-1280, 1999. Previous studies and inventions have
reported the use of ferric compounds in binding with dietary
phosphates, and such ferric compounds are potentially useful for
the treatment of hyperphosphatemia in renal failure patients (U.S.
Pat. No. 5,753,706, 1998; U.S. Pat. No. 6,903,235, 2005; CN
1315174, 2001; Yang W. C., et al., Nephrol. Dial. Transplant
17:265:270 (2002)). Elevated amounts of phosphate in the blood can
be removed by administering compounds such as ferric citrate. Once
in solution, the ferric iron binds phosphate, and the ferric
phosphate compounds precipitate in the gastrointestinal tract,
resulting in effective removal of dietary phosphate from the body.
It is also believed that the absorbed citrate from ferric citrate
is converted to bicarbonate which corrects metabolic acidosis, a
condition common in renal failure patients.
[0005] Int'l App. No. PCT/US2004/004646, filed Feb. 18, 2004,
published under Int'l Publication No. WO2004/074444 on Sep. 2,
2004, discloses a method of preparing ferric organic compounds,
including ferric citrate that remains soluble over a wider range of
pH than previously described preparations, and which have a large
active surface area. However, commercially scalable manufacturing
processes with quality control/analysis measures to ensure and/or
to verify the compliance of the pharmaceutical-grade ferric citrate
or ferric organic compounds with established standards or
specifications were not previously disclosed.
[0006] Accordingly, there exists a need for a scalable process for
synthesizing pharmaceutical-grade ferric organic compounds or
ferric citrate for human use. The process needs to consistently
produce ferric organic compounds or ferric citrate of the required
pharmaceutical grade.
[0007] This invention further discloses dosage for ferric citrate
for treating of a human or non-human subject or patient in need of
the compound. Different routes of administration are explored.
SUMMARY OF THE INVENTION
[0008] In accordance with these and other objects of the invention,
a brief summary of the present invention is presented. Some
simplifications and omission may be made in the following summary,
which is intended to highlight and introduce some aspects of the
present invention, but not to limit its scope. Detailed
descriptions of a preferred exemplary embodiment adequate to allow
those of ordinary skill in the art to make and use the invention
concepts will follow in later sections.
[0009] An embodiment of the invention provides a manufacturing and
quality control process/analysis for making a pharmaceutical-grade
ferric citrate that consistently complies with the established
Manufacture Release Specification. The process of the present
invention can be adapted to produce multi-kilogram batches of
pharmaceutical-grade ferric citrate, and can be readily scaled up
to provide additional manufacturing capacity for ferric
citrate.
[0010] An illustrative embodiment of the manufacturing method may
be exemplified by the following non-limiting sequence of steps for
preparing pharmaceutical-grade ferric citrate comprising the steps
of: (a) dissolving an appropriate amount of Ferric chloride
hexahydrate in water to form a Ferric chloride hexahydrate
solution; (b) dissolving an appropriate amount of NaOH in water to
form a NaOH solution; (c) mixing the Ferric chloride hexahydrate
solution and NaOH solution to form a solution with Fe(OH).sub.3
precipitate; (d) maintaining the pH of the solution with
Fe(OH).sub.3 precipitate above 7.0; (e) isolating the Fe(OH).sub.3
precipitate; (f) washing the Fe(OH).sub.3 precipitate three times
with water; (g) suspending the Fe(OH).sub.3 precipitate in water;
(h) adding citric acid to the Fe(OH).sub.3 precipitate to form a
ferric-organic acid solution; (i) stirring and heating the
ferric-organic acid solution at 90-100.degree. C. for 30 to 120
minutes; (j) removing solids in the ferric-organic acid solution by
adding citric acid; (k) allowing the ferric-organic acid solution
to cool to below 30.degree. C.; (l) maintaining the pH of the
ferric-organic acid solution to between 0.8-1.5; (m) filtering the
ferric-organic acid solution to obtain a liquid filtrate; (n)
mixing acetone and liquid filtrate to form ferric citrate; (o)
isolating ferric citrate; (p) washing ferric citrate with acetone
three times; and (q) drying the ferric citrate.
[0011] A further embodiment provides a large-scale production
scheme for pharmaceutical-grade ferric citrate comprising the steps
of: (a) mixing an appropriate amount of NaOH and Ferric chloride
hexahydrate in a suitable reactor to form a ferric hydroxide slurry
with ferric hydroxide precipitate; (b) maintaining the pH of the
ferric hydroxide slurry to above 7.0; (c) isolating the ferric
hydroxide precipitate from the ferric hydroxide slurry using
pressure filtration; (d) washing the ferric hydroxide precipitate
three times; (e) maintaining the % Cl in the ferric hydroxide
precipitate to below 5%; (f) isolating the washed ferric hydroxide
precipitate using pressure filtration; (g) mixing citric acid with
washed ferric hydroxide precipitate to form a ferric organic acid
solution; (h) stirring and maintaining the temperature of the
ferric organic acid solution at 80.+-.5.degree. C. for 2 hours; (i)
allowing the ferric organic acid solution to cool to 60.degree. C.;
(j) maintaining the pH of the ferric organic acid solution to
between 0.8 to 1.5 and the amount of Fe in the ferric organic acid
solution to .gtoreq.85% of Fe added in step (a); (k) filtering the
ferric organic acid solution using pressure filtration to obtain a
liquid filtrate; (l) mixing the liquid filtrate with acetone to
obtain ferric citrate; (m) isolating ferric citrate using pressure
filtration; (n) washing the ferric citrate with acetone; (o)
isolating the washed ferric citrate using pressure filtration; (p)
drying the washed ferric citrate in fluidized bed dryer; and (q)
maintaining the organic volatile impurities to .ltoreq.1000 ppm
acetone.
[0012] A further embodiment encompasses various intermediate
compositions that may be useful in the preparation of the
pharmaceutical-grade ferric citrate. The intermediate compositions
encompassed herein include solids, liquids or multiphase mixtures.
A liquid intermediate composition comprising the
pharmaceutical-grade ferric citrate may be an aqueous composition
or an organic solvent-based composition. A multiphase composition
may encompass both aqueous and organic phases.
[0013] An additional embodiment encompasses the methods of storing,
packaging and using the various intermediate compositions disclosed
herein.
[0014] An additional embodiment provides pharmaceutically useful
compositions comprising the pharmaceutical-grade ferric citrate.
The pharmaceutically useful composition further comprises any
pharmaceutically acceptable carrier, adjuvant, filler or delivery
vehicle suitable for administering to a subject or human patient,
an effective amount of the pharmaceutical-grade ferric citrate.
[0015] Further embodiments of the pharmaceutical compositions
include, but are not limited to solids, liquids, or semi-solid
forms, such as gels, syrups, chewables or pastes.
[0016] Within the scope of the methods of using the
pharmaceutically useful compositions disclosed herein are effective
doses of the pharmaceutical compositions, in addition to the timing
and modes of administering the pharmaceutical compositions.
[0017] A non-limiting example of a method for using the
pharmaceutical compositions encompasses treating disorders
resulting from elevated blood levels of phosphates, i.e.,
hyperphosphateimia, in a subject or a human patient. Such disorders
are exemplified by, but not limited to, renal failure or the
progression of renal failure, mineralization of soft tissues,
hyperparathyroidism as well as other complications.
[0018] An embodiment encompassed by the invention includes a
pharmaceutical composition comprising:
(a) an amount of a pharmaceutical-grade ferric organic compound
effective to achieve a decrease in the serum phosphate level of a
subject or patient; (b) a pharmaceutically suitable carrier; and
wherein the ferric organic compound complies with at least one of
the limits in the manufacture release specification in Table A.
[0019] The pharmaceutical composition described herein may be
prepared by a method shown in FIG. 1, 2, 3 or 4. Further to these
embodiments are compositions prepared with materials satisfying at
least one limit disclosed in each of the release specifications of
either of the relevant Tables B to F.
[0020] An additional embodiment encompasses compositions of
pharmaceutical-grade ferric citrate, prepared according to methods
comprising the steps of: [0021] (a) dissolving an appropriate
amount of ferric chloride hexahydrate in water to form a ferric
chloride hexahydrate solution; [0022] (b) dissolving an appropriate
amount of NaOH in water to form a NaOH solution; [0023] (c) mixing
the ferric chloride hexahydrate solution and NaOH solution to form
a solution with Fe(OH)3 precipitate; [0024] (d) maintaining the pH
of the solution with Fe(OH).sub.3 precipitate above 7.0; [0025] (e)
isolating the Fe(OH).sub.3 precipitate; [0026] (f) washing the
Fe(OH).sub.3 precipitate three times with water; [0027] (g)
suspending the Fe(OH).sub.3 precipitate in water; [0028] (h) adding
citric acid to the Fe(OH).sub.3 precipitate to form a
ferric-organic acid solution; [0029] (i) stirring and heating the
ferric-organic acid solution at 90-100.degree. C. for 30 to 120
minutes; [0030] (j) removing solids in the ferric-organic acid
solution by adding citric acid; [0031] (k) allowing the
ferric-organic acid solution to cool to below 30.degree. C.; [0032]
(l) maintaining the pH of the ferric-organic acid solution to
between 0.8-1.5; [0033] (m) filtering the ferric-organic acid
solution to obtain a liquid filtrate; [0034] (n) mixing acetone and
liquid filtrate to form ferric citrate; [0035] (o) isolating ferric
citrate; [0036] (p) washing ferric citrate with acetone three
times; [0037] (q) drying the ferric citrate; and [0038] (r)
performing quality control tests as shown in FIG. 1, 2 or 3.
[0039] It is advantageous to scale-up the method of preparation.
Thus, an industrial-scale method is embodied by a method for
large-scale production of pharmaceutical-grade ferric citrate
comprising the steps of: [0040] (a) mixing an appropriate amount of
NaOH and Ferric chloride hexahydrate in a suitable reactor to form
a ferric hydroxide slurry with ferric hydroxide precipitate; [0041]
(b) maintaining the pH of the ferric hydroxide slurry to above 7.0;
[0042] (c) isolating the ferric hydroxide precipitate from the
ferric hydroxide slurry using pressure filtration; [0043] (d)
washing the ferric hydroxide precipitate three times; [0044] (e)
maintaining the % Cl in the ferric hydroxide precipitate to below
5%; [0045] (f) isolating the washed ferric hydroxide precipitate
using pressure filtration; [0046] (g) mixing citric acid with
washed ferric hydroxide precipitate to form a ferric organic acid
solution; [0047] (h) stirring and maintaining the temperature of
the ferric organic acid solution at 80.+-.5.degree. C. for 2 hours;
[0048] (i) allowing the ferric organic acid solution to cool to
60.degree. C.; [0049] (j) maintaining the pH of the ferric organic
acid solution to between 0.8 to 1.5 and the amount of Fe in the
ferric organic acid solution to .gtoreq.85% of Fe added in step
(a); [0050] (k) filtering the ferric organic acid solution using
pressure filtration to obtain a liquid filtrate; [0051] (l) mixing
the liquid filtrate with acetone to obtain ferric citrate; [0052]
(m) isolating ferric citrate using pressure filtration; [0053] (n)
washing the ferric citrate with acetone; [0054] (o) isolating the
washed ferric citrate using pressure filtration; [0055] (p) drying
the washed ferric citrate in fluidized bed dryer; and [0056] (q)
maintaining the organic volatile impurities to .ltoreq.1000 ppm
acetone; [0057] and wherein the ferric citrate complies with at
least one of the limits in the manufacture release specification in
Table A.
[0058] The compositions encompassing pharmaceutical grade ferric
citrate are suitable for treating hyperphosphatemia, or other
disorders characterized by high serum phosphate levels. Therefore,
the invention encompasses treating subjects or patients with
various renal diseases; e.g., End Stage Renal Diseases (ESRD),
Chronic Kidney Disease (CKD) or other relate kidney diseases, or
subjects and patients who are on dialysis but not limited to
hemodialysis.
[0059] In another embodiment, the compositions encompassing
pharmaceutical grade ferric citrate may used to treat subjects or
patients with metabolic acidosis. Other disorders that may be
ameliorated by the conversion of citrate to bicarbonate are also
encompassed by the invention described.
[0060] An embodiment of a method for using the pharmaceutical
composition encompasses treating a human or non-human subject or
patient with chronic kidney disease. There are generally five
clinical stages of chronic kidney disease, numbered 1 to 5, wherein
stage 1 is the least severe and stage 5 the most severe. In the
early stages, e.g., stages 1 and 2, dialysis is not required. As
chronic kidney disease progresses to stage 5, a patient may require
dialysis treatment three times per week. It should be noted that
elevated phosphate levels are observed at all stages of chronic
kidney disease. Therefore, an embodiment of the invention is a
method of treating a subject or person with early or mid-stage
chronic kidney disease, with a composition comprising
pharmaceutical-grade ferric citrate in order to achieve a lower
serum phosphate level.
[0061] It is a further embodiment of the invention to provide a
method of treating a human or non-human subject or patient with
late-stage chronic kidney disease who undergo hemodialysis, by
administering a composition comprising pharmaceutical-grade ferric
citrate. It is known that hemodialysis is not sufficiently
effective in reducing serum phosphate level. The treatment of a
subject or person with late stage kidney disease is applicable
whether or not the subject or person is currently undergoing
hemodialysis treatment.
[0062] An additional embodiment of the invention is a method of
treating a subject or person with chronic kidney disease and
undergoing peritoneal dialysis with the pharmaceutical-grade ferric
citrate-containing compositions described. It is known that
peritoneal dialysis is not sufficiently effective in reducing serum
phosphate levels.
[0063] An additional embodiment is a method for using the
pharmaceutical composition to inhibit or even reverse soft tissue
mineralization, specifically calcification. Hyperphosphatemia may
lead to increased calcium phosphate deposition in hard and soft
tissues by increasing the likelihood of binding with free calcium
to form insoluble calcium phosphate. Therefore, an effective dose
of a composition comprising pharmaceutical-grade ferric citrate may
decrease serum phosphate levels and result in a corresponding
decrease in calcium phosphate deposition.
[0064] It is noteworthy that whereas ferric ion forms insoluble
precipitates with phosphate-containing compounds in the lumen of
the gastroinstestinal tract, the citrate component is absorbed and
functions as a calcium chelator. Because chelated calcium is not
available for calcium phosphate formation, administering
pharmaceutical-grade ferric citrate decreases may lead to
reductions in both serum calcium and phosphate. This may also be
expressed as leading to a decrease in the serum calcium-phosphate
product. Reducing serum calcium and phosphate would be expected to
reduce calcium phosphate deposition. The end result is reversing,
i.e., solubilizing or dissolving, the deposited calcium
phosphate.
[0065] The decalcifying of a calcified soft tissue, e.g., the
sclera of the eye, may be achieved by administering
pharmaceutical-grade ferric citrate. It is known among persons of
ordinary skill in the relevant medical arts that patients with
kidney disease receiving doses of ferric citrate have shown
reversal of calcium deposits on the eye. Therefore, an embodiment
of the invention is directed to the decalcification of soft tissue
such as the eye.
[0066] Kidney stones comprise calcium salts of oxalic acid or
phosphates and are formed by mechanisms similar to those described
above. Thus, pharmaceutical-grade ferric citrate, in another
embodiment of the invention provides a method of treating kidney
stones, i.e., renal calculi, by promoting their dissolution.
[0067] The compositions encompassing pharmaceutical grade ferric
citrate may operate according to more than one mechanism. A
plausible non-limiting mechanism of action may result from the
ferric ion binding phosphate in the GI tract, thus forming an
insoluble ferric phosphate precipitate. This, in turn, may result
in decrease the uptake of phosphate and phosphate-containing
compounds from the GI tract.
[0068] In view of such a mechanism, the administering of
compositions encompassing pharmaceutical grade ferric citrate via
an oral route is encompassed by the inventive methods
described.
[0069] This invention provides a method of reversing, preventing or
stabilizing soft tissue calcification of a subject, comprising
administering to said subject and effective amount of a ferric
citrate compound.
[0070] This invention further provides a method of reversing,
preventing or stabilizing soft tissue calcification of a subject,
comprising administering to said subject and effective amount of a
ferric citrate compound, wherein the ferric citrate compound is
prepared according to a method as shown in FIGS. 1-4.
[0071] This invention provides a method of reversing, preventing or
stabilizing soft tissue calcification of a subject, comprising
administering to said subject and effective amount of a ferric
citrate compound, wherein the ferric citrate compound is prepared
according a method comprising the steps of:
[0072] An embodiment of the invention encompasses tolerable doses
of up to 15 grams per day for ferric citrate capsules and 30 grams
per day for ferric citrate tablets.
[0073] The compositions encompassing pharmaceutical grade ferric
citrate may be administered for varying periods of time. In some
embodiments, the tolerability of the compositions encompassing
pharmaceutical grade ferric citrate allows for long term
administration when necessary.
DETAILED DESCRIPTION OF THE FIGURES
[0074] In drawings which illustrate specific embodiments of the
invention, but which should not be construed as restricting the
spirit or scope of the invention in any way:
[0075] FIG. 1 is a schematic diagram outlining the general method
for synthesis of pharmaceutical-grade ferric citrate including
in-process quality control measures to ensure the final ferric
citrate product complies with the established Manufacture Release
Specification as shown in Table A.
[0076] FIG. 2 is a schematic diagram outlining a method of making
pharmaceutical-grade ferric citrate according to the invention.
[0077] FIG. 3 shows an overview of scalable pharmaceutical-grade
ferric citrate manufacturing and quality control process according
to the invention.
[0078] FIG. 4 is a schematic diagram of scalable
pharmaceutical-grade ferric citrate manufacturing and quality
control process according to the invention.
[0079] FIG. 5 shows the representative proton NMR spectrum for a
pharmaceutical-grade ferric citrate according to the invention.
[0080] FIG. 6 shows the representative FTIR spectrum for
pharmaceutical-grade ferric citrate according to the invention.
[0081] FIG. 7 is a comparison of intrinsic dissolution rates at pH
1.0 and 8.0 for pharmaceutical grade and chemical grade ferric
citrate.
[0082] FIG. 8 is a schematic diagram outlining the general method
for synthesis of pharmaceutical-grade ferric organic compound
including in-process quality control measures to ensure the final
ferric organic compound complies with established Manufacture
Release Specification.
[0083] FIG. 9 is a summary of clinical results for
pharmaceutical-grade ferric citrate
[0084] FIG. 10 is a summary of the efficacy data for
pharmaceutical-grade ferric citrate
[0085] FIG. 11 is a summary of the safety data from a clinical
study
[0086] FIG. 12 is a comparison of the safety profiles of chemical
grade and pharmaceutical grade ferric citrates
[0087] FIG. 13 is a comparison of the efficacy profiles of chemical
grade and pharmaceutical grade ferric citrates
[0088] FIG. 14 shows a bar graph of the relationship between the
rate of dialysis patient mortality and hyperphosphatemia
DETAILED DESCRIPTION OF THE INVENTION
[0089] In drawings which illustrate specific embodiments of the
invention, but which should not be construed as restricting the
spirit or described in detail to avoid unnecessarily obscuring the
invention. Accordingly, the specification and drawings are to be
regarded in an illustrative, rather than a restrictive, sense.
[0090] Throughout this application, references are made to the
United States Pharmacopeia (USP), and the latest edition of the
USP, USP 28, is hereby incorporated by reference into this
application in its entirety.
[0091] This invention provides a method of preparing
pharmaceutical-grade ferric citrate, comprising the steps of: (a)
dissolving an appropriate amount of Ferric chloride hexahydrate in
water to form a Ferric chloride hexahydrate solution; (b)
dissolving an appropriate amount of NaOH in water to form a NaOH
solution; (c) mixing the Ferric chloride hexahydrate solution and
NaOH solution to form a solution with Fe(OH).sub.3 precipitate; (d)
maintaining the pH of the solution with Fe(OH).sub.3 precipitate
above 7.0; (e) isolating the Fe(OH).sub.3 precipitate; (f) washing
the Fe(OH).sub.3 precipitate three times with water; (g) suspending
the Fe(OH).sub.3 precipitate in water; (h) adding citric acid to
the Fe(OH).sub.3 precipitate to form a ferric-organic acid
solution; (i) stirring and heating the ferric-organic acid solution
at 90-100.degree. C. for 30 to 120 minutes; (j) removing solids in
the ferric-organic acid solution by adding citric acid; (k)
allowing the ferric-organic acid solution to cool to below
30.degree. C.; (l) maintaining the pH of the ferric-organic acid
solution to between 0.8-1.5; (m) filtering the ferric-organic acid
solution to obtain a liquid filtrate; (n) mixing acetone and liquid
filtrate to form ferric citrate; (o) isolating ferric citrate; (p)
washing ferric citrate with acetone three times; and (q) drying the
ferric citrate.
[0092] This invention provides a method for scalable or large-scale
production of pharmaceutical-grade ferric citrate comprising the
steps of: (a) mixing an appropriate amount of NaOH and Ferric
chloride hexahydrate in a suitable reactor to form a ferric
hydroxide slurry with ferric hydroxide precipitate; (b) maintaining
the pH of the ferric hydroxide slurry to above 7.0; (c) isolating
the ferric hydroxide precipitate from the ferric hydroxide slurry
using pressure filtration; (d) washing the ferric hydroxide
precipitate three times; (e) maintaining the % Cl in the ferric
hydroxide precipitate to below 5%; (f) isolating the washed ferric
hydroxide precipitate using pressure filtration; (g) mixing citric
acid with washed ferric hydroxide precipitate to form a ferric
organic acid solution; (h) stirring and maintaining the temperature
of the ferric organic acid solution at 80.+-.5.degree. C. for 2
hours; (i) allowing the ferric organic acid solution to cool to
60.degree. C.; (j) maintaining the pH of the ferric organic acid
solution to between 0.8 to 1.5 and the amount of Fe in the ferric
organic acid solution to .gtoreq.85% of Fe added in step (a); (k)
filtering the ferric organic acid solution using pressure
filtration to obtain a liquid filtrate; (l) mixing the liquid
filtrate with acetone to obtain ferric citrate; (m) isolating
ferric citrate using pressure filtration; (n) washing the ferric
citrate with acetone; (o) isolating the washed ferric citrate using
pressure filtration; (p) drying the washed ferric citrate in
fluidized bed dryer; and (q) maintaining the organic volatile
impurities to .ltoreq.1000 ppm acetone.
[0093] In an embodiment, the ferric chloride hexahydrate complies
with the release specification as shown in Table B; the citric acid
complies with the release specification as shown in Table F; the
water complies with the release specification as shown in Table D;
the acetone complies with the release specification as shown in
Table E; and the sodium hydroxide complies with the release
specification as shown in Table C.
[0094] In another embodiment, the ferric citrate is dried using a
fluidized bed dryer or is dried under vacuum.
[0095] In a further embodiment, the process as described above
further comprises testing the ferric citrate for compliance with
the release specification as shown in Table A. In a further
embodiment, testing comprises performing at least one test selected
from the group consisting of: assay content purity of ferric
citrate and ferric citrate monohydrate; assay content of citric
acid; assay content of detectable ferric citrate related
substances; assay content of ferric ion; elemental iron impurity
test; limit of ferrous iron test; loss on drying test; hydrate test
(water content by differential scanning calorimetry); hydrate test
(water content by karl Fischer Titration); trace or heavy metals
test (As, Ca, Cd, Cu, Fe, Hg, Na, Pb, Sr, Zn); limit of oxalic acid
test; identification A for ferric salts test; identification B by
FTIR test; insoluble substances test; limit of ammonium test; limit
of chloride test; limit of nitrate test; limit of tartrate test;
residue on ignition test; organic volatile impurities test; and
microbial, mold and yeast test.
[0096] This invention provides a pharmaceutical-grade ferric
citrate prepared according to the methods described above.
[0097] This invention provides a composition comprising the ferric
citrate prepared according to the methods described above for
treating hyperphosphatemia or metabolic acidosis.
[0098] This invention provides a composition prepared according to
the methods described above for treating disorders responsive to
ferric organic compound therapy.
[0099] This invention provides a pharmaceutical-grade ferric
citrate prepared according to the methods described above, wherein
the ferric citrate produces the peak as shown in FIG. 6 when
subjected to NMR spectroscopy analysis.
[0100] This invention provides a pharmaceutical-grade ferric
citrate prepared according to the methods described above, wherein
the ferric citrate possesses the dissolution rates as shown in FIG.
8.
[0101] This invention provides a pharmaceutical-grade ferric
citrate prepared according to the methods described above, wherein
the ferric citrate produces the spectral data as shown in FIG. 7
when subjected to Fourier Transform Infrared Spectrometry (FTIR)
spectrum analysis.
[0102] This invention provides a composition comprising the ferric
citrate as described above for treating hyperphosphatemia or
metabolic acidosis.
[0103] This invention provides a composition comprising the ferric
acid as describe above for treating disorders responsive to ferric
organic compound therapy.
[0104] This invention provides a pharmaceutical-grade ferric
citrate prepared by the process comprising the steps as shown in
FIG. 1-4.
[0105] The pharmaceutical-grade ferric citrate according to the
invention is useful for treating a subject suffering from
hyperphosphatemia, metabolic acidosis or a disorder responsive to
ferric organic compound therapy. In an embodiment, the subject is a
human being.
[0106] The invention also provide a use for a composition
comprising pharmaceutical-grade ferric citrate effective for one or
more of the following uses, [0107] (a) treating hyperphosphatemia;
[0108] (b) decreasing mortality rate in dialysis patients; [0109]
(c) treating metabolic acidosis; [0110] (d) inhibiting calcium
phosphate deposition; [0111] (e) decreasing serum calcium-phosphate
product ([Ca].times.[P]) [0112] (f) decreasing serum calcium
levels; [0113] (g) reversing calcification of soft tissue; and
[0114] (h) aiding to dissolve a kidney stone.
[0115] The use may further encompass at least partly relying on
reducing serum levels of calcium and phosphate ions.
[0116] The uses as stated above may apply to soft tissue such as a
blood vessel or an eye.
[0117] The uses as stated may be carried out by administering over
a long-term.
[0118] The invention allows for the above-stated uses to be
achieved wherein the use is accompanied by less gastronintestinal
adverse side effects than if the composition comprised chemical
grade ferric citrate.
[0119] In accordance with the above-stated uses, the invention
provides for a method for treating a disorder characterized by a
high serum phosphate level comprising administering an effective
amount of a composition comprising pharmaceutical-grade ferric
citrate.
[0120] The invention also provides for the method wherein an
effective amount of pharmaceutical-grade ferric citrate is
administered in the form of a tablet, a powder, a suspension, an
emulsion, a capsule, a lozenge, a granule, a troche, a pill, a
liquid, a spirit, or a syrup.
[0121] The invention also provides for the method wherein the
effective amount of pharmaceutical-grade ferric citrate is from 2
to 100 grams per day, preferably between 4 and 60 grams per
day.
[0122] In some embodiments, the method may provide a daily
effective amount of 2, 4, 6, or 8 grams.
[0123] In general, hyperphosphatemia is prevalent in patients with
chronic renal failure and in patients on dialysis. There is also
evidence that indicate elevated serum phosphorus,
calcium-phosphorus product (Ca.times.P) and parathyroid hormone
(PTH) levels contribute to increased incidence of vascular,
visceral, peripheral vascular and soft tissue calcification in
renal disease patients
[0124] Thus, it is an additional novel feature of the claimed
invention to prevent or reverse calcification in renal disease
patient or in a normal person. For example, dissolving kidney
stones that may accompany renal failure.
[0125] Phosphorous exerts a negative impact on vascular
calcification by direct participation in the Ca.times.P and
indirectly in the pathogenesis and progression of hyperthyroidism.
Serum calcium and phosphorous are metastable under normal
circumstances, which means that their concentrations are not
sufficient to produce spontaneous precipitation. However, once the
calcification process begins, the concentrations are sufficient to
support crystal proliferation.
[0126] Available evidence confirms a high prevalence of underlying
vascular disease and structural heart disease in patients with
severe chronic renal failure. These structural lesions are then
exposed to elevated serum phosphorus, Ca.times.P, and PTH(1).
[0127] Factors which are considered likely to contribute to
elevated serum phosphorus and Ca.times.P include administration of
calcium-containing phosphorus binders. The calcium-containing
phosphorus binders, such as calcium acetate are prescribed to many
new hemodialysis (HD) and peritoneal dialysis (PD) patients, thus
providing a large source of exogenous calcium to the GI tract.
[0128] Calcification also extends beyond renal disease patients and
can include anyone who is over the age of 40. While the leading
cause of death in the United States is acute myocardial infarction
and stroke, hypercholesteromia contribute to only 15% of the deaths
in this category and 85% is caused by ventricular
calcification.
[0129] It has been shown that abnormalities in serum phosphorous,
Ca.times.P and PTH levels can result in vascular, visceral and/or
soft tissue calcification. For example, calcifications of
myocardium, coronary arteries, cornea can lead to the development
of a number of clinically significant complications including
myocardial ischemia, myocardial infarction, impaired myocardial
function, congestive heart failure, cardiac valve insufficiency and
blindness.
[0130] Accordingly, there exists a need for methods of managing or
reducing serum phosphorous as a means of treating numerous medical
disorders. The method includes administering a phosphate binder
which does not adversely affect serum calcium levels and does not
cause toxic side effects in the patient.
EXAMPLES
[0131] In examples which are intended to illustrate embodiments of
the invention but which are not intended to limit the scope of the
invention:
Example 1. General Method for Synthesis of a Pharmaceutical-Grade
Ferric Citrate
[0132] Referring to FIG. 1, which shows a general method of
synthesis of the pharmaceutical-grade ferric citrate according to
the invention, the flow chart shows implementation of quality
control measures at selected stages of the synthesis process to
ensure the final ferric citrate product complies with the
Manufacture Release Specification as shown in Table A or any
established Manufacture Release Specification for
pharmaceutical-grade ferric citrate which have been approved or are
suitable for human use. Other quality control measures or
procedures, which are readily apparent to one of ordinary skill in
the art, can be used or incorporated into the pharmaceutical-grade
synthesis process to maintain the quality and purity of the final
product and to increase the efficiency and yield of the synthesis
process. See, for example, QC10 and QC11 in FIG. 1.
[0133] Examples of quality control measures employed in the
synthesis process include: (QC4) maintaining pH of the ferric
hydroxide slurry above 7.0; (QC5) maintaining the % Cl in ferric
hydroxide precipitate below 5%; (QC7) maintaining the pH of the
mixture between 0.8-1.5 and the Fe in mixture .gtoreq.85% of total
Fe added after adding citric acid to ferric hydroxide precipitate;
and (QC9) maintaining the level of acetone to .ltoreq.1000 ppm
during the drying stage.
[0134] In an embodiment, the raw materials, i.e., ferric chloride,
deionized water, citric acid, acetone, sodium hydroxide, must pass
release specifications, such as those provided on Table B-F, before
they can be used in the synthesis process. See FIG. 1, QC1-QC3, QC6
and QC8.
Example 1A. General Method for Synthesis of a Pharmaceutical-Grade
Ferric Organic Compounds
[0135] Referring to FIG. 10, which shows a general method of
synthesis of the pharmaceutical-grade ferric organic compounds
according to the invention, the flow chart shows implementation of
quality control measures at selected stages of the synthesis
process to ensure the final ferric citrate product complies with
established Manufacture Release Specification for
pharmaceutical-grade ferric organic compounds which have been
approved or are suitable for human use. Other quality control
measures or procedures, which are readily apparent to one of
ordinary skill in the art, can be used or incorporated into the
pharmaceutical-grade synthesis process to maintain the quality and
purity of the final product and to increase the efficiency and
yield of the synthesis process. See, for example, QC10A and QC11A
in FIG. 10.
[0136] Examples of quality control measures employed in the
synthesis process include: (QC4A) maintaining pH of the ferric
hydroxide slurry above 7.0; (QC5A) maintaining the % Cl in ferric
hydroxide precipitate below 5%; (QC7A) maintaining the pH of the
mixture between 0.8-1.5 and the Fe in mixture .gtoreq.85% of total
Fe added after adding organic acid to ferric hydroxide precipitate;
and (QC9A) maintaining the level of organic solvent to .ltoreq.1000
ppm during the drying stage.
[0137] In an embodiment, the raw materials, i.e., ferric iron salt,
deionized water, organic acid, organic solvent, alkaline metal
hydroxide, must pass release specifications before they can be used
in the synthesis process. See FIG. 1, QC1A-QC3A, QC6A and QC8A. The
organic acid can comprise citric acid, acetic acid, isocitric acid,
succinic acid, fumaric acid, tartaric acid, or any other suitable
organic acid. The organic solvent can comprise ethanol, methanol,
butanol, acetone, isopropyl alcohol, tetrahydrofuran, or any other
suitable organic solvent.
Example 2. Solubility Profile of Ferric Organic Compounds According
to the Invention
[0138] The ferric organic compounds produced according to the
methods described above are more soluble than commercially
available ferric organic compounds, over a wider range of pH
levels. This increase in solubility of the ferric organic compounds
of the present invention is believed to be a result of the unique
significantly large active surface area of the ferric organic
compounds of the present invention. For example, at pH 8.0, the
intrinsic dissolution rate of ferric citrate of the present
invention is 3.08 times greater than the commercially available
ferric citrate. See Table 1.
[0139] The intrinsic dissolution rates of commercially available
ferric citrate were compared with the ferric citrate of the present
invention. The intrinsic dissolution rate is defined as the
dissolution rate of pure substances under the condition of constant
surface area. The dissolution rate and bioavailability of a drug
substance is influence by its solid state properties:
crystallinity, amorphism, polymorphism, hydration, solvation,
particle size and particle surface area. The measured intrinsic
dissolution rate is dependent on these solid-state properties and
is typically determined by exposing a constant surface area of a
material to an appropriate dissolution medium while maintaining
constant temperature, stirring rate, and pH. The intrinsic
dissolution rates are presented in Table 1.
TABLE-US-00001 TABLE 1 Intrinsic dissolution rates of ferric
citrate at 37.degree. C. in solutions of pH 8 Mean Rate of
Intrinsic Intrinsic Acetone Dissolution Dissolution Addition Rates
Rates Sample (ml/min) (mg/cm2/min) (mg/cm2/min) RFS-12 (sigma/ 10.0
0.83 0.83 commercially available) STM-134 10.0 1.88 3.08 (reference
material) PAN031203A 10.0 3.82 (experimental batch 1) PAN031203B
10.0 4.00 (experimental batch 2) PAN031203C 9.5 2.68 (experimental
batch 3) PAN031203D 40 2.95 (experimental batch 4) PAN031203E 4.4
3.13 (experimental batch 5)
[0140] For example, the BET active surface area of the ferric
citrate of the present invention is at least 16 times larger than
the commercially available ferric citrate. See Table 2.
[0141] The analysis of active surface area is based on BET theory
which describes the phenomenon of mass and energy interaction and
phase changes during gas adsorption onto solid surfaces and in pore
spaces. In BET active surface area measurement, the volume of a
monolayer of gas is determined which allows the surface area of the
sample to be determined using the area occupied by a single layer
of adsorbed gas molecule. Table 4 is a comparison of the active
surface area of the ferric citrate of the present invention
compared to the active surface area of commercially available
ferric citrate compounds.
TABLE-US-00002 TABLE 2 BET active surface areas of various forms of
ferric citrate Mean BET Dissolution Active Rates Surface Sample
(mg/cm2/min) Area RFS-12-1 (sigma/commercially 0.76 0.61 available)
RFS-12-2 (sigma/commercially available) STM-134-1 (reference
material 1) 2.47 16.17 STM-134-2 (reference material 2) STM-182-1
(lab-scale 500 g batch 1) 2.61 19.85 STM-182-2 (lab-scale 500 g
batch 2)
Example 3. Use of Ferric Organic Compounds According to the
Invention in the Treatment of Disorders
[0142] The ferric organic compounds produced according to the
methods described above are useful in the treatment of
hyperphosphatemia, metabolic acidosis, and any other disorders
responsive to ferric organic compound therapy. Because the ferric
organic compounds of the present invention are more soluble than
commercially available ferric organic compounds, smaller amounts of
the ferric organic compounds of the present invention can be used
to effectively treat patients suffering from such disorders.
[0143] Improved aqueous solubility is particularly relevant to the
use of the ferric organic compounds of the present invention in the
treatment of disorders responsive to ferric organic compound
therapy. Because the ferric organic compounds of the present
invention are more soluble, they will be more effective when taken
orally, and therefore can be taken in lower doses. The ferric
organic compounds of the present invention are more soluble over a
wider pH range than commercially available ferric organic
compounds; therefore, the ferric organic compounds of the present
invention can be more effective by being soluble in the small
intestine.
[0144] For example, in an experiment simulating the alkaline
condition in the small intestine, the ferric citrate of the present
invention showed better dissolution rate than the commercially
available ferric citrate. It is suggested that the ferric citrate
of the present invention can be more effective by being more
soluble in the small intestine. See Table 1. As a result, patients
can take lower doses of medication with lower incidences of side
effects.
[0145] In one embodiment of the invention, the ferric citrate of
the present invention has a significantly higher rate of aqueous
solubility under physiological conditions than commercially
available forms of ferric citrate, and therefore the ferric citrate
of the present invention is believed to provide a significant
improvement in the orally effective use of ferric citrate at a
reduced dosage. By reducing the orally effective dose of ferric
citrate, it is believed that the ferric citrate of the present
invention will provide a lower incidence of ulcerative
gastrointestinal adverse effects associated with commercially
available ferric citrate compounds. In addition, it is believed
that the increased rate of dissolution of the ferric citrate of the
present invention will provide a more rapid onset of action in
binding to dietary phosphate.
[0146] The ferric organic compounds of the present invention can be
administered in a number of forms, including orally administrable
forms, which can comprise the ferric organic compounds of the
present invention alone or in combination with a pharmaceutically
acceptable carrier. The orally administrable form includes, but is
not limited to, a tablet, a powder, a suspension, an emulsion, a
capsule, a granule, a troche, a pill, a liquid, a spirit, or a
syrup. The composition can be administered to human beings or other
animals suffering from illnesses responsive to ferric organic
compound therapy.
Example 4. A Method of Making a Pharmaceutical-Grade Ferric
Citrate
[0147] The present invention describes a process for manufacturing
pharmaceutical-grade ferric citrate suitable as an active
pharmaceutical ingredient for human use. An overview of the Ferric
Citrate Manufacture Flow Chart is shown in FIG. 1. For a specific
example, pharmaceutical-grade ferric citrate was produced using the
procedure described below. Also see FIG. 2.
4.1. Preparation of Ferric Chloride Solution
[0148] Weigh 550 g of ferric chloride hexahydrate (correct for CoA
purity) into a 1 L beaker.
[0149] Transfer the ferric chloride hexahydrate into a 4 L
Erlenmeyer flask.
[0150] Measure 1.1 L of deionized water using a graduated cylinder.
Use a small portion of the deionized water to rinse the beaker and
transfer the water into the 4 L Erlenmeyer flask. Transfer the
remaining water into the Erlenmeyer flask.
[0151] Stir solution using a magnetic stirring bar until completely
dissolved. The solution is a dark yellow to dark brown color.
4.2. Preparation of Sodium Hydroxide Solution
[0152] Weigh 244 g of sodium hydroxide (correct for CoA purity)
into a 500 mL beaker.
[0153] Transfer the sodium hydroxide into a 2 L Erlenmeyer
flask.
[0154] Measure 1.1 L of deionized water using a graduated cylinder.
Use a small portion of the deionized water to rinse the beaker and
transfer the water into a 4 L Erlenmeyer flask. Transfer the
remaining water into the Erlenmeyer flask slowly.
[0155] In a fumehood, stir the solution using a stirring bar while
adding the water and stir until completely dissolved. The solution
is clear and colorless.
[0156] Cool solution to below 30.degree. C. using a water bath.
4.3. Preparation of Ferric Hydroxide Intermediate
[0157] Place a magnetic stirring bar into the ferric chloride
solution and place the flask in a water bath. Set up on a stirring
plate and start the stirring plate at a low speed.
[0158] Add slowly the sodium hydroxide solution to the ferric
chloride solution (at a rate of less than 20 mL/min) using an
addition funnel and control the temperature of the reaction mixture
below 40.degree. C. using the water bath and the rate of addition
of sodium hydroxide.
[0159] Continue to cool the brown viscous mixture to below
30.degree. C. using the water bath.
[0160] The final pH should be above 7. Use a suitable volume of 5 M
aqueous sodium hydroxide solution to correct the pH if not above 7.
Measure and record the final pH. A dark brown precipitate of ferric
hydroxide is formed.
[0161] If required, cool the brown viscous mixture to below
30.degree. C. using the cold water bath and filter the ferric
hydroxide suspension through 1 mm size stainless steel filter to
break up large precipitates.
[0162] Transfer equal amounts of ferric hydroxide suspension into
four 500 mL centrifuge containers. Balance the weight of each
centrifuge container using a top-loading balance before
centrifugation.
[0163] Centrifuge the ferric hydroxide suspension at 1500 rpm and
25.+-.5.degree. C. for 5 minutes. Discard the supernatant.
[0164] Measure 2.5 L of deionized water using a graduated cylinder
and use approximately 1 L of water to re-suspend the ferric
hydroxide precipitate from the centrifuge containers.
[0165] Transfer the ferric hydroxide suspension into a 4 L
Erlenmeyer flask fitted with a 1 mm size stainless steel filter
over a glass funnel. Use the remaining 1.5 L of deionized water to
rinse the containers and wash the precipitate retained on the
stainless steel filter.
[0166] Wash the precipitate two more times by repeating the steps
beginning with "Transfer equal amounts . . . ."
[0167] After the third wash, recover the precipitate by repeating
the steps beginning with "Transfer equal amounts . . . " and ending
with "Centrifuge the ferric hydroxide suspension . . . ."
[0168] Re-suspend the precipitate in 150 mL of deionized water.
4.4. Preparation of Ferric Citrate
[0169] Homogenize the ferric hydroxide precipitate using a
mechanical stirrer for 5 min in a 2 L Erlenmeyer flask.
[0170] Weigh 490 g of citric acid (correct for CoA purity) into a
500 mL beaker.
[0171] Place a stir bar in the 2 L Erlenmeyer flask in an oil bath
and stir at high speed.
[0172] Add the citric acid into the ferric hydroxide
suspension.
[0173] Stir the solution for 30 minutes.
[0174] Heat the mixture at 90 to 100.degree. C. (in oil bath) until
the color changes from orange-brown to a clear black-brown (for 30
to 120 min) or until ferric hydroxide precipitate is dissolved.
[0175] Take 1 mL aliquot of the reaction mixture in a 6 mL glass
test tube and centrifuge at 1500 rpm and 25.+-.5.degree. C. for 5
minutes. Proceed to the next step if no precipitate is observed. If
some precipitate is observed add 10 to 34 g citric acid to the
mixture and continue heating for 10 to 30 min.
[0176] Terminate the heating and cool the mixture to below
30.degree. C. Measure the pH of the reaction mixture; it should be
pH 0.8 to 1.5.
[0177] Transfer equal amounts of the reaction mixture into four 500
mL centrifuge containers and balance the weight of each container
using a top-loading balance.
[0178] Centrifuge the reaction mixture at 1500 rpm and
25.+-.5.degree. C. for 5 minutes. Transfer and pool all the ferric
citrate supernatant to a clean 4 L Erlenmeyer flask.
[0179] Repeat the above 2 steps for all of the ferric citrate
reaction mixture.
[0180] Place one-half of the ferric citrate supernatant in a 4 L
Erlenmeyer flask and stir with a magnetic stir bar at high
speed.
[0181] Add slowly (over 20 min) 3.5 L of acetone (accurate volume
acetone calculated as five fold the supernatant volume) and stir
for an additional 10 min. A light-beige color precipitate
forms.
[0182] Transfer the suspension into four 500 mL centrifuge
containers and balance the weight of each container using a
top-loading balance.
[0183] Centrifuge the ferric citrate suspension at 1500 rpm and
25.+-.5.degree. C. for 5 minutes.
[0184] Transfer and pool all the ferric citrate precipitate to a
clean 4 L Erlenmeyer flask.
[0185] Repeat the above 4 steps with the second half of the ferric
citrate supernatant.
[0186] Pool all ferric citrate precipitate, add 1.4 L of acetone
and stir for 5 min.
[0187] Transfer the suspension into four 500 mL centrifuge
containers and balance the weight of each container using a
top-loading balance.
[0188] Centrifuge the suspension at 1500 rpm and 25.+-.5.degree. C.
for 5 minutes.
[0189] Repeat the above 2 steps until all suspension is
centrifuged.
[0190] Transfer and pool all the ferric citrate precipitate to a
clean 4 L Erlenmeyer flask.
[0191] Repeat the above 5 steps two additional times (total of 3
washes).
[0192] Label and weigh drying trays, and record their weight.
[0193] Transfer the ferric citrate precipitate onto the drying
dishes and dry at ambient temperature (25.+-.5.degree. C.) for 16
hours.
[0194] Place the drying trays with precipitate into a vacuum oven
and dry at ambient temperature (25.+-.5.degree. C.) and under
vacuum (about 20 mm Hg) for 8 to 16 hours (until the material
appears ready for grinding).
[0195] Reduce the particle size of the ferric citrate in a
porcelain mortar and pestle.
[0196] Place the ferric citrate powder into a vacuum oven and dry
at ambient temperature (25.+-.5.degree. C.) and under vacuum (about
20 mm Hg) for 8 to 24 hours, until the material appears ready for
sieving.
[0197] Finely reduce the ferric citrate particle size in a
porcelain mortar and pestle. Screen the ferric citrate powder
through a 45 mesh size (355 micron) sieve.
[0198] Transfer the ferric citrate powder into drying trays and
place the trays in an oven to dry at 25.+-.5.degree. C. and under
high vacuum until the material appears dry (20 to 48 hours).
[0199] Transfer the powder into pre-weighed plastic amber
containers.
[0200] Label and store the containers at ambient temperature and
protected from light.
Example 5. Method for Scalable Manufacture of Pharmaceutical-Grade
Ferric Citrate
[0201] The present invention provides a scalable manufacturing of
pharmaceutical-grade ferric citrate. Preferably, the ferric citrate
manufacturing process is capable of producing at least 125 kg
batches of pharmaceutical-grade ferric citrate. An overview of the
ferric citrate manufacturing is shown in FIG. 3. Details of the
synthesis of ferric citrate are shown in FIG. 4.
[0202] The scalable manufacturing process further employs fluidized
bed dryer for drying wet ferric citrate and for attaining release
specifications for organic volatile impurities. See Table A for the
Manufacture Release Specifications for Pharmaceutical-Grade Ferric
Citrate.
Example 6. A Pharmaceutical-Grade Ferric Citrate
[0203] This invention provides a pharmaceutical-grade ferric
citrate which complies with the Manufacture Release Specifications
as shown below in Table A. The pharmaceutical-grade ferric citrate
of consistent purity and quality can be prepared using the
manufacturing process of the present invention. See FIGS. 1-4 for
the schematic diagram of the ferric citrate manufacturing and
quality control process. The ferric citrate manufacturing and
quality control process can be readily scaled to produce
multi-kilogram batch sizes or scaled up to a manufacturing
scale.
TABLE-US-00003 TABLE A Manufacture Release Specification for
Pharmaceutical-Grade Ferric Citrate Test Item Method Limit of
Specification Appearance Visual Light brown to beige powder Purity
of solid Calculate based on LC/MS - NLT 90% w/w state ferric
citrate flow injection anhydrous basis quantitation and profile,
based on USP 25 <621>, <731>, <1086>, <736>
Assay content of LC/MS - flow injection Run and report ferric
citrate non- profile, based on USP 25 as % w/w related substances
<621>, <731>, <1086>, anhydrous basis in solution
state <736> (attach table summary) Assay content purity LC/MS
- flow injection NLT 70% w/w of ferric citrate quantitation, based
on anhydrous basis and water adduct in USP 25 <621>,
<731>, solution state <1086>, <736> Assay content
of LC/MS - flow injection NLT 10% w/w citric acid related
quantitation, based on anhydrous basis substance in USP 25
<621>, <731>, solution state <1086>, <736>
Assay content of LC/MS - flow injection Run and report other ferric
citrate profile, based on USP 25 as % w/w related substances
<621>, <731>, <1086>, anhydrous basis in solution
state <736> (attach table (excluding citric summary) acid)
Assay content of Based on USP 25 ferric NLT 16% w/w fresh ferric
iron sulfate assay weight basis Limit of ferrous Gravimetric method
using NMT 1% w/w fresh iron potassium ferricynide, weight basis
based on USP 25 <191> Loss on drying USP 25 <731> NMT
20% Hydrate (water Karl Fischer Titration NMT 20% content) USP 25
<921> water determination, Method Ia (Direct Titration)
Identification Method A: based on USP 25 Dark blue <191>
ferric salt precipitate with K4Fe(CN)6 TS; reddish brown ppt with
excess 1N NaOH; deep red color not destroyed by mineral acids with
NH4SCN TS Sample solution gives light red color with pyridine and
acetic anhydride Limit of chloride Based on USP 25 Ferric NMT 5%
sulfate procedures Reside on ignition Modified USP 25 <281>
Run and report Organic Volatile Based on USP 25 <467> Acetone
not more Impurities than 1000 ppm Limit of acid Gravimetric Not
more than insoluble determination, based on 0.02% w/w fresh
substances USP 25, ferric sulfate weight basis Trace/heavy USP 25
method <231> or As <0.3 ppm metals equivalent Others: run
and ICP for Zn, Cu, Sr, Ca, report Na GFAAS for As Lead, Cadmium
ICP-MS Pb < 5 ppm Cd < 2 ppm Mercury Cold vapor/AA Hg <
0.3 ppm Total iron content ICP NLT 16% w/w fresh weight basis
Microbial/Mold USP Method <61> and Yeast Salmonella
Salmonella = negative E. Coli E. Coli = negative Coliforms Total
Coliforms < 3 cfu/g Total aerobic count Total aerobic count <
10 cfu/g Total combined mold and Total mold and yeast < 20 cfu/g
yeast
TABLE-US-00004 TABLE B Ferric chloride hexahydrate Release
Specifications Test Item Method Limit of Specification Appearance
Visual Yellow to yellowish brown powder, crystals or chunks
Identification - USP 25 <191> Yield dark blue precipitate
with Ferric salts potassium ferrocyanide TS Form reddish brown
precipitate with excess 1N NaOH Red deep color with ammonium
thiocyanate TS and color not destroyed by dilute mineral acids
Identification - USP 25 <191> Aqueous solution of ferric
chloride Chloride yields with 0.1N silver nitrate TS a white,
cruddy precipitate, which is insoluble in nitric acid but is
soluble in a slight excess of 6N ammonium hydroxide Heavy metals
ICP-MS As < 0.1 ppm Cd < 0.1 ppm Hg < 0.1 ppm Pb < 0.1
ppm Assay - Ferric USP 25, Assay >18% iron ferric sulfate, p.
2303
TABLE-US-00005 TABLE C Sodium Hydroxide Release Specifications Test
Item Method Limit of Specification Appearance Visual White pellets,
odorless Identification - USP25, <191> No precipitate is
formed with Sodium potassium carbonate A dense precipitate is
formed with potassium pyroantimonate An intense yellow color to a
non- luminous flame
TABLE-US-00006 TABLE D Deionized Water Release Specification Test
Item Method Limit of Specification Appearance Visual Clear,
colorless and odorless Mineral scan ICP-MS As < 0.001 ml/L Cd
< 0.0002 ml/L Pb < 0.001 ml/L Hg < 0.02 .mu.g/L Total
Organic Standard <1 mg/L Carbon Method for the Examination of
Water and Wastewater, 20.sup.th ed. Total Hardness Standard <4
mg/L Method for the Examination of Water and Wastewater, 20.sup.th
ed. Total Plate USP 25 method <10 cfu Count <61> Total
Coliform USP 25 method <3 cfu Count <61>
TABLE-US-00007 TABLE E Acetone Release Specification Test Item
Method Limit of Specification Appearance Visual Clear colorless
liquid Identification - USP 25, The IR absorption of a thin film
Acetone p. 2502, between KBr plates exhibits a FTIR strong band at
about 5.8 .mu.m; a strong region of absorption between 6.8 and 7.5
.mu.m, with maxima at about 7.0 and 7.3 .mu.m; a strong maximum at
about 8.2 .mu.m; and a weak maxima at about 9.2 and 11.0 .mu.m.
Assay From NLT 99.5% manufacturer's Certificate of Analysis (result
from GC method preferred) Aldehyde From NMT 0.002% (as HCHO)
manufacturer's Certificate of Analysis Isopropyl From NMT 0.05%
alcohol manufacturer's Certificate of Analysis Methanol From NMT
0.05% manufacturer's Certificate of Analysis Residue after From NMT
5 ppm evaporation manufacturer's Certificate of Analysis Acids From
NMT 0.0003 meq manufacturer's Certificate of Analysis (result from
titrimetric test) Bases From NMT 0.0006 meq manufacturer's
Certificate of Analysis (result from titrimetric test) Water From
NMT 2% manufacturer's Certificate of Analysis Insoluble From
filtered through .ltoreq.0.45 .mu.m substances manufacturer's
filter Certificate of Analysis or filtered through .ltoreq.0.45
.mu.m filter
TABLE-US-00008 TABLE F Citric Acid Release Specification Test Item
Method Limit of Specification Appearance Visual White or colorless
crystals or powder Identification - USP 25 <191> A light red
color is produced Citrate
Example 8. Final Product Manufacture Release Testing Methods
[0204] The following tests are performed to ensure the final ferric
citrate product prepared according to the method or process of the
present invention complies with the established Manufacture Release
Specification as shown in Table A. The Manufacture Release
Specification may be readily modified or revised by one of ordinary
skill in the art following the teaching of this invention to
enhance the purity and safety of the pharmaceutical-grade ferric
citrate for human use. [0205] (a) Based on USP 25 <191>
Gravimetric method using potassium ferricyanide, p. 1918--Limit of
Ferrous Iron in Ferric Citrate [0206] (b) Based on USP 25, ferric
sulfate assay, p. 728--Limit of Chloride in Ferric Citrate [0207]
(c) Based on USP 25, ferric sulfate assay, p. 728--Limit of Acid
Insoluble Substances in Ferric Citrate [0208] (d) Based on USP 25,
ferric sulfate assay, p. 728--Assay Content of Ferric Iron in
Ferric Citrate [0209] (e) Based on USP 25
<467>--Determination of Acetone in Ferric Citrate Samples by
GClFID Headspace [0210] (f) Based on USP 25 <191> Ferric
Salts; Citrate, p. 1918--Identification of Ferric Citrate [0211]
(g) Based on USP 25 <621>, p. 1988-1995, <731>,
<1086>, p. 2157-2159, <736>, p. 2029-2033--LCMS
Flow-Injection Quantitation and Profile of Ferric Citrate and
Related Substances [0212] (h) USP 25 <731> Loss on Drying
[0213] (i) USP 25 <921> Water Determination, Method Ia
(Direct Titration) [0214] (j) ICP for Zn, Cu, Sr, Ca, Na and total
iron [0215] (k) GFAAS for As [0216] (l) ICP-MS for lead and cadmium
[0217] (m) Cold vapor/AA for mercury [0218] (n) Residue on ignition
[0219] (o) Microbial/mold and yeast
Example 9 Methods of Using and Testing the Pharmaceutical-Grade
Ferric Citrate in Patients In Vivo
A. Handling and Forms of Test Compositions
[0220] Ferric citrate is supplied in 500 mg capsules, whereas the
placebo will be provided in identical-looking capsules
(indistinguishable from those containing the active drug); the
placebo capsules will contain sorbitol and colorant to match the
powder color of the active capsules. The placebo capsule shells
will be identical to the active capsule shells.
Storage
[0221] All study drug supplies must be stored under secure
conditions and are not to be used after their expiration date,
which is imprinted on the study drug container. The study drugs
should be kept under controlled conditions (15 to 30.degree. C.; 59
to 86.degree. F.) in a tightly closed container, protected from
light.
Dosage
[0222] A recent pilot study compared ferric citrate (3 g daily) to
calcium carbonate (3 g daily) for reducing serum P0.sub.4 in
patients with End Stage Renal Disease (ESRD). Although ferric
citrate caused a significant decrease in serum P04, it was not as
effective as calcium carbonate. This dose of ferric citrate was
associated with mild, but tolerable GI symptoms.
[0223] As shown in FIGS. 12 and 13, treatments using
pharmaceutical-grade ferric citrate provide several advantages over
chemical grade ferric citrate. In general, while
pharmaceutical-grade ferric citrate demonstrates an efficacy
approximately equal to that of chemical grade ferric citrate, it
achieves this result with less adverse side effects than chemical
grade ferric citrate.
[0224] FIG. 12 also indicates that adverse side effects associated
with administering pharmaceutical-grade ferric citrate were not
statistically different from those associated with the placebo. An
advantage of this safety profile is that an individual patient may
have his dosing of pharmaceutical-grade ferric citrate titrated
over a broad range of doses with less concern about side effect. In
this way, a patient's individual treatment may be tailored to suit
his specific needs and tolerances.
[0225] The doses of ferric citrate chosen for study or treatment
may be from 1 to 30 grams of ferric citrate per day. In part, this
may depend on the nature of the formulation provided. For example,
ferric citrate capsules may be administered up to a daily dose of
about 15 grams/day, whereas the tablet form may be administered up
to 30 grams/day. Thus, there is a very broad range of dosing
regimens encompassed by the invention.
Titration of Optimal Dosage for a Subject
[0226] In the context of this invention, the term "subject" refers
to either a human or non-human animal.
[0227] The optimal dosage of an individual subject or groups may be
determined as follows. A dose of approximately one or two grams per
day is merely suggested as an illustrative starting dose. The daily
dose may be increased as needed until the desired result is
observed.
[0228] The intent of the invention is to not limit the dose range
employed. Therefore, depending on the subject(s) the daily dose
administered may approximate thirty, forty, fifty, sixty, seventy,
eighty, ninety or one hundred grams per day. The safety profile of
the pharmaceutical-grade ferric citrate allows the implementation
of a broad range of doses.
[0229] Further, it is the intent of the invention to not be limited
to capsules and tablets as oral formulations. It is known in the
art that a wide variety of oral formulations may be adapted for use
with the invention.
Illustrative Example of a Dosage Regimen
[0230] An non-limiting example of a dosing regimen is provided
below. This is not meant to limit the invention as to how an
effective amount of ferric citrate is selected, or the form in
which it is provided or the frequency of administering the
composition per day. The following merely illustrates how ferric
citrate and placebo may be administered; e.g., as 500 mg capsules
of identical appearance. All patients may receive (in a blinded
fashion) 4 capsules with each of three meals, on a daily basis, for
28 days. Patients will be instructed to take the study medication
within 10 minutes of finishing their meals (breakfast, lunch, and
dinner).
[0231] The number of placebo, and active capsules to be taken at
each meal, are as follows:
Placebo Arm of the Study
[0232] 4 placebo capsules, with breakfast 4 placebo capsules, with
lunch 4 placebo capsules with dinner
Ferric Citrate 2 g Per Day Arm of the Study
[0233] 1 ferric citrate capsule and 3 placebo capsules with
breakfast 1 ferric citrate capsule and 3 placebo capsules with
lunch 2 ferric citrate capsules and 2 placebo capsules with
dinner
Ferric Citrate 4 g Per Day Arm
[0234] 2 ferric citrate capsules and 2 placebo capsules with
breakfast 3 ferric citrate capsule and 1 placebo capsule with lunch
3 ferric citrate capsules and 1 placebo capsule with dinner
Ferric Citrate 6 g Per Day Arm
[0235] 4 ferric citrate capsules with breakfast 4 ferric citrate
capsules with lunch 4 ferric citrate capsules with dinner
B. Clinical Schedule and Assessments
Duration of Study Treatment
[0236] Each patient's participation in the trial lasts for up to 8
weeks: the screening period (approximately 1-2 weeks), a 1-2 week
washout, and 4 weeks of treatment with study medication.
Screening Visit 1 (Study Days -30 to -15)
[0237] The following procedures will be performed at the first
screening visit:
1. Medical history, including concomitant medications. 2.
Demographic data. 3. Physical examination, including height,
weight, and vital signs. 4. Dietary interview, using 24 hour recall
method, to assess dietary intake of calcium and phosphorous, three
times during screening period, to include one dialysis day, one
non-dialysis day, and one weekend day. Note: Dietary interview may
be also performed, in part or in whole, during the washout period.
5. Laboratory assessment: [0238] Hematology: complete blood count
(CBC) with differential, platelets. [0239] Chemistries: sodium,
potassium, chloride, bicarbonate, blood urea nitrogen (BUN),
creatinine, glucose (random), aspartate transaminase (AST), alanine
transaminase (ALT), alkaline phosphatase (ALP), total bilirubin,
total protein, albumin, serum calcium, serum phosphate, magnesium
[0240] Total and LDL cholesterol levels [0241] Serum (3-HCG for
women of childbearing potential [0242] Iron panel: serum iron,
ferritin, transferrin saturation percentage, and total iron binding
capacity. 6. 12-lead ECG. 7. Patients will be given instructions
for the Washout
Period (Study Days -14 to -1):
[0243] a. All phosphate-binding agents will be discontinued at Day
-14 b. Any iron therapy (oral or intravenous) will be discontinued
at Day -14 c. Patients who have been receiving a stable dose of
vitamin D or calcitriol for I month prior to enrollment will be
instructed to maintain their current dose throughout the study d.
Patients will be advised to avoid changes in diet, calcium or
magnesium containing antacids (other medications).
Screening Visit 2 (Study Days -7+/-1 Day)
1. Laboratory Assessment:
Serum P0.sub.4
[0244] Note: Patients with a Day -7 serum P0.sub.4 .gtoreq.5.5
mg/dL and .ltoreq.10 mg/dL may be randomized before the 2-week
washout is complete. The day of randomization will automatically
become Day 0. Note: Patients with a Day -7 phosphate level of
.gtoreq.10 mg/dL will be removed from the study and instructed to
resume their pre-study medications.
Study Day 0 (Randomization and Dosing)
[0245] 1. Physical examination, including weight and vital signs.
2. Adverse event query. 3. Concomitant medication query. 4.
Baseline Laboratory assessments: [0246] Serum P04 [0247] Serum Ca
[0248] Iron panel: serum iron, ferritin, transferrin saturation
percentage, and total iron binding capacity Note: The Baseline
Laboratory Assessments may be done up to 3 days prior to Day 0 5.
Patients with a P0.sub.4 level 0.5 mg/dL and 5 10 mg/dL will be
randomized and a 15-day supply of study medication will be
dispensed. Note: Patients should be instructed to begin taking
study medication within 10 minutes of completing their next meal on
Day 0.
Study Day 14 (Midpoint Evaluation)
[0249] The following procedures will be performed at Study Day
14+/-1 day.
1. Physical examination including weight and vital signs. 2.
Adverse event query. 3. Concomitant medication query. 4. Dispense
an additional 15-day supply of study medication. All returned
capsules should be counted and recorded in the Case Report Form. 5.
Laboratory assessment: [0250] Hematology: CBC with differential,
platelets. [0251] Chemistries: sodium, potassium, chloride,
bicarbonate, BUN, creatinine, glucose (random), AST, ALT, ALP,
total bilirubin, total protein, albumin, calcium, phosphate,
magnesium. [0252] Iron panel: serum iron, ferritin, transferrin
saturation percentage, and total iron binding capacity. [0253]
Total and LDL cholesterol levels. Note: Patients with a Day 14
phosphate level of >10 mg/dL will be removed from the study and
instructed to resume their pre-study medications.
Study Day 28 (End of Study Evaluation)
[0254] The following procedures will be performed at Study Day
28+/-1 day or on the day of early termination.
1. Physical examination including weight and vital signs 2. Adverse
event query. 3. Concomitant medication query. 4. Laboratory
assessment: a. Hematology: CBC with differential, platelets b.
Chemistries: sodium, potassium, chloride, bicarbonate, BUN,
creatinine, glucose (random), AST, ALT, ALP, total bilirubin, total
protein, albumin, calcium, phosphate, magnesium. c. Total and LDL
cholesterol levels [0255] d. Iron panel: serum iron, ferritin,
transferrin saturation percentage, and total iron binding capacity.
5. 12-lead ECG 6. Patients will be instructed to resume their
pre-study medications after completing the study.
C. Data Management and Analysis
[0256] GloboMax will be the primary data management, monitoring,
and coordinating center. Case report forms (CRF) will be provided
for each subject. Subjects will not be identified by name or
initials on CRFs. The CRF will be monitored at the clinical sites
and collected by GloboMax's study monitor. Audited CRFs will be
used to create electronic data files.
[0257] Three major categories of endpoints reflect biochemical and
clinical issues being addressed at the outset. Additional clinical
and biochemical issues are addressed as they arise. Therefore, the
endpoints are not meant to limit the totality of relevant findings
and measurements collected in these, or future studies.
Primary Endpoints (see FIGS. 9-10)
[0258] The change in serum P0.sub.4 concentration at Days 14 and 28
from baseline.
Secondary Endpoints (see FIGS. 9-10)
[0258] [0259] The change in serum calcium concentration at Days 14
and 28 from baseline. [0260] The change in iron, ferritin,
transferrin saturation percentage, and total iron binding capacity
at Days 14 and 28 from baseline. [0261] The change in the
Ca'PO.sub.4 product at Days 14 and 28 from baseline.
[0262] It is further noted that in comparison to chemical grade
ferric citrate, the pharmaceutical grade ferric citrate
demonstrates similar efficacy. See FIG. 13. However, the safety
profiles indicate that the pharmaceutical grade generally results
in less adverse clinical effects. See FIG. 13.
Safety Endpoints (See FIG. 11)
[0263] Safety will be monitored by recording adverse events (FIG.
11) and the results of physical examinations, vital signs and
laboratory tests at each study visit.
[0264] Specific rules for withdrawal from the study, based on
laboratory data, have also been set up to ensure patient safety. A
nonlimiting example of such criteria is illustrated by the
following:
[0265] If a patient's serum phosphate level increases to .gtoreq.10
mg/dL at any time during the study period, the patient will be
withdrawn from the study.
[0266] Specific studies have also shown that pharmaceutical grade
ferric citrate possesses similar efficacy to chemical grade ferric
citrate. (See FIG. 13). However, the pharmaceutical grade generally
affords a significantly more desirable safety profile as shown in
FIG. 12. This indicates an important advance in regulating serum
phosphate levels.
* * * * *