U.S. patent application number 16/376907 was filed with the patent office on 2020-07-09 for ferric citrate dosage forms.
The applicant listed for this patent is KERYX BIOPHARMACEUTICALS, INC.. Invention is credited to Henry Trong Le.
Application Number | 20200215019 16/376907 |
Document ID | / |
Family ID | 42738229 |
Filed Date | 2020-07-09 |
United States Patent
Application |
20200215019 |
Kind Code |
A1 |
Le; Henry Trong |
July 9, 2020 |
FERRIC CITRATE DOSAGE FORMS
Abstract
The disclosure relates to ferric citrate tablets and dosage
forms.
Inventors: |
Le; Henry Trong; (Englewood
Cliffs, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KERYX BIOPHARMACEUTICALS, INC. |
Cambridge |
MA |
US |
|
|
Family ID: |
42738229 |
Appl. No.: |
16/376907 |
Filed: |
April 5, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15159008 |
May 19, 2016 |
10300039 |
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16376907 |
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13255326 |
Sep 8, 2011 |
9387191 |
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PCT/US10/42788 |
Jul 21, 2010 |
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15159008 |
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61227124 |
Jul 21, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2077 20130101;
A61K 9/2095 20130101; A61K 9/2059 20130101; A61P 3/12 20180101;
A61K 9/2013 20130101; A61K 31/295 20130101; A61K 9/2054 20130101;
A61P 3/00 20180101 |
International
Class: |
A61K 31/295 20060101
A61K031/295; A61K 9/20 20060101 A61K009/20 |
Claims
1. A tablet comprising granule particles, said granule particles
comprising ferric citrate and a binder, wherein the mean surface
area to mass ratio of said granule particles is equal to or greater
than 1 m.sup.2 per gram.
2. The tablet of claim 1, wherein the mean surface area to mass
ratio of said granule particles is equal to or greater than 5
m.sup.2 per gram.
3. The tablet of claim 1 wherein the mean surface area to mass
ratio of said granule particles is equal to or greater than 10
m.sup.2 per gram.
4. The tablet of claim 1 wherein the tablet comprises at least 70
weight percent ferric citrate.
5. The tablet of claim 1 wherein the tablet comprises at least 80
weight percent ferric citrate.
6. The tablet of claim 1 wherein the tablet comprises at least 90
weight percent ferric citrate.
7. The tablet of claim 1 wherein the binder comprises one or more
of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose
(HPMC), sodium alginate, alginic acid, guar gum, acacia gum,
xanthan gum, carbolpol, cellulose gum (carboxymethyl cellulose),
ethyl cellulose, maltodextrin, PVP/VA, povidone, microcrystalline
cellulose, starch (partially or fully pregelatinized starch) and
methyl cellulose.
8. The tablet of claim 1, wherein the LOD % water of the tablet is
less than 20% water w/w.
9. The tablet of claim 1, wherein the LOD % water of the tablet is
less than 15% water w/w.
10. The tablet of claim 1, wherein the LOD % water of the tablet is
less than 10% water w/w.
11. The tablet of claim 1 further comprising a disintegrant
selected from one or more of microcrystalline cellulose,
croscarmellose sodium, crospovidone, sodium starch glycolate, and
starch.
12. The tablet of claim 1 further comprising a lubricant selected
from one or more of magnesium stearate, calcium stearate, and
sodium stearyl fumarate.
13. The tablet of claim 1 wherein the tablet comprises: between
approximately 65% and 92% ferric citrate; between approximately
4.5% and 30% binder; and between 0.5% and 3% lubricant.
14. The tablet of claim 1 wherein the binder comprises
pregelatinized starch.
15. The tablet of claim 12, wherein the lubricant comprises calcium
stearate, and sodium stearyl fumarate.
16. The tablet of claim 1 wherein at least 80% of the ferric
citrate in the tablet is dissolved in a time less than or equal to
60 minutes as measured by test method USP <711>.
17. The tablet of claim 1 wherein the tablet comprises
approximately 1000 mg of ferric citrate.
18. The tablet of claim 1 wherein the tablet comprises
approximately 667 mg of ferric citrate.
19. The tablet of claim 1 wherein the tablet comprises
approximately 500 mg of ferric citrate.
20. A method of preparing a tablet according to claim 1, the method
comprising: mixing the ferric citrate with one or more binders
under conditions in which the LOD % water does not exceed 25% to
form ferric citrate granules; tableting the ferric citrate granules
to form a tablet.
21. The method according to claim 20, wherein said granule
particles have a mean surface area to mass ratio greater than 1
m.sup.2 per gram.
22. The method according to claim 21, wherein the mean surface area
to mass ratio of said granule particles is equal to or greater than
10 m.sup.2 per gram.
23. The process of claim 18, wherein the mixing step comprises
fluid bed granulation.
24. The process of claim 18, wherein the mixing step comprises high
shear granulation.
25. The method according to claim 20, further comprising heating
said tablet above 50.degree. C.
26. A method for the prophylaxis or treatment of hyperphosphatemia
comprising administering the tablet of claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This Patent Cooperation Treaty patent application claims
priority to U.S. Provisional Patent Application No. 61/227,124
filed Jul. 21, 2009, which is incorporated by reference herein for
all purposes in its entirety.
FIELD
[0002] The field of the disclosure generally relates to
pharmaceutical compositions of ferric citrate, methods for their
use in treating medical conditions, and processes for their
manufacture.
BACKGROUND
[0003] U.S. Pat. No. 5,753,706 discloses that ferric citrate
compounds can be used to control phosphate metabolism and prevent
metabolic acidosis in patients. The contents of U.S. Pat. No.
5,753,706 are incorporated herein in its entirety by reference.
Ferric citrate compounds can be used with patients suffering from
renal failure associated with hyperphosphatemia or patients
predisposed to development of a hyperphosphatemic condition. Ferric
citrate also is used as a food supplement and additive. Ferric
citrate is characterized as a light brown to beige powder, odorless
and slightly ferruginous tasting. According to the Merck Index,
ferric citrate is slowly but completely soluble in cold water and
readily soluble in hot water but diminishes in solubility with
age.
[0004] U.S. Pat. No. 6,903,235 discloses that ferric citrate is
commercially available in the form of a combination of iron and
citric acid of indefinite composition. The contents of U.S. Pat.
No. 6,903,235 are incorporated herein in its entirety by reference.
The '235 patent explains that the indefinite composition is likely
due to difficulties encountered in its preparation but that those
knowledgeable in the art understand and necessarily accept that
commercially available ferric citrate contains different molar
ratios of iron and citric acid and also contains different amounts
of hydrate.
[0005] WO 2004/074444 discloses processes for making ferric organic
compounds, such as ferric citrate, with enhanced dissolution rates.
WO 2007/022435 is a continuation-in-part of WO 2004/074444 and
discloses processes for making ferric organic compounds soluble
over a wide pH range and having a large surface area. WO 2007089577
is directed to methods of treating soft tissue calcification using
ferric organic compounds, such as a ferric citrate compound. WO
2007089571 is directed to methods of treating chronic kidney
disease using ferric organic compounds, such as ferric citrate
compounds.
SUMMARY
[0006] In one aspect, the disclosure is directed to a tablet
including ferric citrate. In some embodiments, the tablet can
include at least 65 weight percent ferric citrate.
[0007] In another aspect, the disclosure is directed to a tablet
comprising granule particles. The granule particles include ferric
citrate and a binder, and the mean surface area to mass ratio of
the granule particles is equal to or greater than 1 m.sup.2 per
gram. In various embodiments, the mean surface area to mass ratio
of said granule particles is equal to or greater than 5 m.sup.2 per
gram or 10 m.sup.2 per gram.
[0008] In another aspect, the tablet can include at least 70 weight
percent ferric citrate, at least 80 weight percent ferric citrate,
or at least 90 weight percent ferric citrate.
[0009] In another aspect, the binder can be one or more of
hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose
(HPMC), sodium alginate, alginic acid, guar gum, acacia gum,
xanthan gum, carbolpol, cellulose gum (carboxymethyl cellulose),
ethyl cellulose, maltodextrin, PVP/VA, povidone, microcrystalline
cellulose, starch (partially or fully pregelatinized starch) and
methyl cellulose.
[0010] In another aspect, the tablet can include various additional
components including, for example, one or more disintegrants and/or
one or more lubricants. The disintegrant can be one or more of
microcrystalline cellulose, croscarmellose sodium, crospovidone,
sodium starch glycolate, and starch. The lubricant can be one or
more of magnesium stearate, calcium stearate, sodium stearyl
fumarate, polyethylene glycol (molecular weight above 3350), sodium
lauryl sulfate, talc, mineral oil, leucine, and poloxamer. In some
embodiments, the tablet can include between approximately 65% and
92% ferric citrate, between approximately 4.5% and 30% binder, and
between 0.5% and 3% lubricant. The binder can have disintegrant
properties. The binder can be pregelatinized starch.
[0011] In another aspect, the tablet can be between approximately
65% and 92% ferric citrate, between approximately 4.5% and 30%
binder, between approximately 1.5% and 15% disintegrant, and
between 0.5% and 3% lubricant.
[0012] Various additional components in the tablet can include
microcrystalline cellulose, pregelatinized starch and sodium
stearyl fumarate. In one embodiment, the ferric citrate can be
present at approximately 85 weight percent, the microcrystalline
cellulose present at approximately 4 weight percent, the
pregelatinized starch present at approximately 9 weight percent,
and the sodium stearyl fumarate present at approximately 2 weight
percent.
[0013] In another aspect, the tablet can have between approximately
10% and 60% of ferric citrate dissolved in about 15 minutes,
between approximately 30% and 90% of ferric citrate dissolved in
about 30 minutes and at least approximately 60% of the ferric
citrate dissolved in about 60 minutes in a dissolution test
according to test method USP <711>. The tablet can have a
dissolution of at least 90% within 30 minutes in a dissolution test
according to test method USP <711>. The tablet can show a
dissolution of at least 90% within 60 minutes in a dissolution test
according to test method USP <711>.
[0014] The tablet can show a disintegration time of less than 30
minutes in a disintegration test according to test method USP
<701>. The tablet can show a disintegration time of greater
than 30 minutes in a disintegration test according to test method
USP <701>.
[0015] The tablet can include approximately 1000 mg of ferric
citrate, approximately 667 mg of ferric citrate, approximately 500
mg of ferric citrate, approximately 250 mg of ferric citrate, or
approximately 125 mg of ferric citrate.
[0016] In various aspects, the LOD (loss on dried) % water in the
tablet is less than 20% water w/w. In other aspects, the LOD %
water of the tablet is less than 15% water w/w. In still other
aspects, the LOD % water of the tablet is less than 10% water
w/w.
[0017] In various aspects, at least 80% of the ferric citrate in
the tablet is dissolved in a time less than or equal to 60 minutes
as measured by test method USP <711>.
[0018] In another aspect, the tablet includes a disintegrant. In
certain embodiments, the disintegrant can be selected from one or
more of microcrystalline cellulose, croscarmellose sodium,
crospovidone, sodium starch glycolate, and starch.
[0019] In another aspect, the tablet includes a lubricant. In
certain embodiments, the lubricant can be selected from one or more
of magnesium stearate, calcium stearate, and sodium stearyl
fumarate.
[0020] In another aspect, the disclosure is directed to a method of
preparing a ferric citrate tablet. The method includes mixing the
ferric citrate with one or more binders under conditions in which
the LOD % water does not exceed 25% to form ferric citrate
granules. Granulation can be performed by any method known in the
art (e.g. fluid bed granulation or high shear granulation). The
ferric citrate granules are then tableted.
[0021] In another aspect, the tablets are heated to above
50.degree. C. after tableting.
[0022] The tablets can be used for the prophylaxis or treatment of
a variety of diseases or disease states, including, but not limited
to, hyperphosphatemia.
[0023] Embodiments of the method can include one or more of the
features described above or herein.
[0024] The details of various embodiments are set forth in the
accompanying drawings and the description below. Features and
advantages of various embodiments are apparent from the
description, the drawings, and the claims.
DESCRIPTION OF THE DRAWINGS
[0025] Those skilled in the art will understand that the drawings,
described herein, are for illustration purposes only. The drawings
are not intended to limit the scope of the present disclosure.
[0026] FIG. 1 is a chart showing hardness as a function of
compression force for Formulations 1-5.
[0027] FIG. 2 is a chart showing friability as a function of
compression force for Formulations 1-5.
[0028] FIG. 3 is a chart showing disintegration time as a function
of compression force for Formulations 1-5.
[0029] FIG. 4 is a chart showing dissolution time for Formulations
1 and 3-5.
[0030] FIG. 5 is a chart showing hardness as a function of
compression force for Formulations 6-8 and 11.
[0031] FIG. 6 is a chart showing friability as a function of
compression force for Formulations 6-8 and 11.
[0032] FIG. 7 is a chart showing disintegration time as a function
of compression force for Formulations 6-8 and 11.
[0033] FIG. 8 is a chart showing dissolution time for Formulations
6-8 and 11.
[0034] FIG. 9 shows the dissolution time different tablets that
were pre-dried and post-dried.
DETAILED DESCRIPTION
[0035] Disclosed herein are ferric citrate-containing tablets. In
various embodiments, the tablets include ferric citrate
formulations that meet certain dissolution, tableting and
disintegration standards. In various aspects, the tablet
formulations can include ferric citrate as the active ingredient
and a binder. The formulations also can include a lubricant and/or
a disintegrant (which, in some embodiments, can be the same as the
binder).
[0036] Tablets
[0037] In one aspect, the formulation is a tablet that includes
ferric citrate and a binder. As is used herein, a "tablet" is a
material produced by compression force, such as with a tableting
machine. In other embodiments the formulation or tablet can include
ferric citrate, a binder, a lubricant and a disintegrant. The
tablet or formulation can be used as a prophylaxis or treatment for
hyperphosphatemia by administering the tablet or formulation in an
effective amount or amounts known in the art.
[0038] The formulation can be characterized as highly drug loaded
with the ferric citrate present in the formulation at values of
greater than approximately 65% by weight of the formulation,
greater than approximately 70% by weight of the formulation and as
high as approximately 92% of the formulation. Intermediate values
such as approximately 80% by weight ferric citrate, approximately
85% by weight ferric citrate and approximately 90% by weight ferric
citrate also can be used in the ferric citrate formulation. The
characteristics of the tablet produced at these highly loaded
weight percentages are controlled by variables such as binder,
binder amount, disintegrant, disintegrant amount, formulation
method used (e.g., granulation, direct compression), tableting
parameters, etc. Thus if a tablet is made and it has a slight
amount of lamination or capping, by varying one or more of the
above variables, the lamination or capping can be corrected.
[0039] In various embodiments, the tablet formulation contains one
or more components selected from among one or more binders, one or
more lubricants, and one or more disintegrants.
[0040] The binder can be any binder known in the art. Without
limitation, examples of the binder can include one or more of
hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose
(HPMC), sodium alginate, alginic acid, guar gum, acacia gum,
xanthan gum, carbolpol, cellulose gum (carboxy methyl cellulose),
ethyl cellulose, maltodextrin, PVP/VA, povidone, microcrystalline
cellulose, starch (partially or fully pregelatinized starch) and
methyl cellulose. The maltodextrin, PVP/VA, and methyl cellulose
function as immediate release binders when used in the ferric
citrate formulations.
[0041] It also should be understood that combinations of binders
can be used to control and vary the effect of the binder. For
example, a binder system can be made up of hydroxypropyl cellulose
and polyvinyl pyrrolidone (povidone) with or without
microcrystalline cellulose. One or both of the hydroxypropyl
cellulose and povidone can be replaced with pregelatinized
starch.
[0042] In various aspects, the tablet can include a lubricant. As
an example of a lubricant for the ferric citrate formulations,
magnesium stearate, calcium stearate, sodium stearyl fumarate and
combinations can be used. Other suitable lubricants include one or
more of polyethylene glycol (molecular weight above 3350), sodium
lauryl sulfate, talc, mineral oil, leucine, and poloxamer.
[0043] In various aspects, the tablet can include a disintegrant.
The disintegrant can be included in the formulation. The
disintegrant can be the same as or different from the binder. By
way of example and not limitation, microcrystalline cellulose has
both binder and disintegrant properties and microcrystalline
cellulose can be use as the sole binder/disintegrant in the
formulation. Examples of other suitable disintegrants include
croscarmellose sodium, crospovidone, sodium starch glycolate, and
starch.
[0044] The binder can be present in the formulation in an amount
ranging from approximately 4.5% by weight to approximately 30% by
weight. The disintegrant can be present in the formulation in an
amount ranging from approximately 1.5% by weight to approximately
15% by weight. In various embodiments, some non-starch
disintegrants are often used at lower ranges, e.g., as low as 0.25%
and thus the disintegrant present in the formulation can be as low
as 0.25% in some conditions.
[0045] The lubricant can be present in the formulation in an amount
ranging from approximately 0.5% by weight to approximately 3% by
weight. It should be understood that some components, such as
microcrystalline cellulose, can function with both disintegrant and
binder properties.
[0046] The weight of individual tablets can depend upon the final
dosage to be produced; e.g. 125 mg, 250 mg, 500 mg, 667 mg, 750 mg
and 1,000 mg of Ferric citrate.
[0047] In various embodiments, tablets are coated to a weight gain
of approximately 2% to 5% using an Opadry suspension or equivalent
in a perforated pan coater. As noted above, calcium stearate and
Opadry purple can be replaced with or used with a different
lubricant or coating system, respectively.
[0048] Tablets Having High Surface Area Per Unit Mass
[0049] In one variation, the disclosed tablets contain granule
particle size having a significantly higher mean surface area per
unit mass than previous ferric citrate formulations. It has been
discovered that the increased surface area per unit volume results
in immediate release dissolution times (greater than 80% at 60
minutes after administration as determined by United States
Pharmacopeia (USP) test <711, described in United States
Pharmacopeia Compendium of Standards, USP 30 NF 25, Vol. 1 p.
276-284 (2007), which is incorporated herein by reference in its
entirety). Without wishing to be limited to a specific theory or
mode of action, the increased granular surface area of granules in
the tablet results in an increased amount of ferric citrate exposed
to the solvent. The immediate release dissolution times are
significantly reduced in a reduced tablet size.
[0050] In additional variations, the tablets disclosed herein can
be designed to have a mean granule particle surface area to mass
ratio equal to or greater than 1 square meter per gram. In further
variations, the tablet has a mean granule particle surface area to
mass ratio equal to or greater than 2 square meters per gram. In
further variations, the formulation has a mean granule particle
surface area to mass ratio equal to or greater than 4 square meters
per gram. In further variations, the formulation has a mean granule
particle surface area to mass ratio equal to or greater than 6
square meters per gram. In further variations, the formulation has
a mean granule particle surface area to mass ratio equal to or
greater than 8 square meters per gram. In further variations, the
formulation has a mean granule particle surface area to mass ratio
equal to or greater than 10 square meters per gram. In further
variations, the formulation has a mean granule particle surface
area to mass ratio equal to or greater than 15 square meters per
gram. In further variations, the formulation has a mean granule
particle surface area to mass ratio equal to or greater than 20
square meters per gram. In further variations, the formulation has
a mean granule particle surface area to mass ratio equal to or
greater than 30 square meters per gram. In further variations, the
formulation has a mean granule particle surface area to mass ratio
equal to or greater than 40 square meters per gram. In further
variations, the formulation has a mean granule particle surface
area to mass ratio equal to or greater than 50 square meters per
gram. The increased surface area per particle in a tablet resulted
in a significantly increased dissolution rate.
[0051] In other variations, the tablets have reduced water content.
In one embodiment, the granular water content as measured by LOD %
is less than 20%. In another embodiment, the granular water content
as measured by LOD % is less than 19%. In another embodiment, the
granular water content as measured by LOD % is less than 18%. In
another embodiment, the granular water content as measured by LOD %
is less than 17%. In another embodiment, the granular water content
as measured by LOD % is less than 16%. In another embodiment, the
granular water content as measured by LOD % is less than 15%. In
another embodiment, the granular water content as measured by LOD %
is less than 14%. In another embodiment, the granular water content
as measured by LOD % is less than 13%. In another embodiment, the
granular water content as measured by LOD % is less than 12%. In
another embodiment, the granular water content as measured by LOD %
is less than 11%. In another embodiment, the granular water content
as measured by LOD % is less than 10%. In another embodiment, the
granular water content as measured by LOD % is less than 9%. In
another embodiment, the granular water content as measured by LOD %
is less than 8%. In another embodiment, the granular water content
as measured by LOD % is less than 7%. In another embodiment, the
granular water content as measured by LOD % is less than 6%. In
another embodiment, the granular water content as measured by LOD %
is less than 5%.
[0052] As will be understood to those of skill in the art, in
various embodiments LOD is a method of thermogravimetric moisture
determination: In thermogravimetric processes the moisture of a
material includes substances that volatilize during warming, and
therefore contribute to the material's loss of mass. Alongside
water this may also include alcohol or decomposition products. When
using thermogravimetric measurement methods (drying using infrared,
halogen, microwaves or ovens) no distinction is made between water
and other volatile components.
[0053] Friability
[0054] Friability generally measures the mechanical strength of
tablets. During the process of coating, transportation, packing,
and other processes. tablets can lose some weight. To measure the
weight loss the samples are counted and weighed.
[0055] In various embodiments, friability test is performed as
described in United States Pharmacopeia Compendium of Standards
(2007), which is incorporated herein by reference in its
entirety.
[0056] Method of Making Tablets
[0057] In one tableting method, the tablets can be prepared in
three steps. First, granules of ferric citrate and binder are
formed. Second, a lubricant is added to the formulation before
tableting. Third, the tablet is dried after an optional coating
step.
[0058] Granulation
[0059] Ferric Citrate, such as pharmaceutical grade ferric citrate
described, for example, in U.S. Pat. No. 6,903,235 B2, can be
granulated by any method known in the art. Exemplary methods of
granulation include fluid bed granulation, high shear granulation
and direct compression granulation.
[0060] In embodiments in which the moisture of the formulation was
brought to the level above 25% LOD at any point resulted in a
substantially lower surface area per gram of particle. This can be
accomplished, for example, by limiting the quantity of water
introduced, or by air blowing and monitoring the amount of water in
a formulation.
[0061] To increase the surface area to mass ratio of ferric citrate
particles to greater than 1 square meter per gram, or in other
embodiments greater than 10 square meter per gram, the moister
content of the granules is maintained at below 25% LOD throughout
formation of granules. In certain variations, the moister content
of the granules is maintained at below 24% LOD, 23% LOD, 22% LOD,
21% LOD, or 20% LOD, throughout formation of granules.
[0062] Without wishing to be held to a particular mechanism or mode
of action, it is hypothesized that keeping the amount of water
below 25% LOD during granulation maintains granules with a high
surface area per mass ratio. The addition of water in higher
amounts at any time during the granulation process results in
formation of larger granules with a lower mean surface area to mass
ratio. The lower surface area to mass reduces the dissolution rate
below the rate for an immediate release formulation. The measured
lower mean surface area to mass ratio of granules results in slower
dissolution, and release characteristics.
[0063] In various embodiments, it has been observed that the
reduced surface area to weight ratio of the ferric citrate
formulation is irreversible after addition of moisture at above 25%
LOD. Accordingly, the percent water is kept below 25% during
granulation in various embodiments.
[0064] Blending In various embodiments, one or more lubricants can
be blended with the granules. In various embodiments, a
non-limiting list of lubricants includes stearates such as calcium
stearate and magnesium stearate, sodium stearyl fumarate, stearic
acid, talc, polyethylene glycol, hydrogenated vegetable oils,
aluminum stearate, sodium benzoate, sodium acetate, sodium
chloride, leucine, Carbowax, and Magnesium Lauryl Sulfate. Certain
starches, such as starch 1500, can also be considered lubricants,
as they have some lubricant properties when used in direct
compression application. Any lubricant known in the art can be
used, including any of those disclosed in the Handbook of
Pharmaceutical Excipients fifth edition, incorporated herein by
reference in its entirety. Multiple lubricants can be combined.
[0065] In certain embodiments, a greater quantity of lubricant than
is ordinarily used in the art can be used. It has been discovered
that surprisingly, the quantity of lubricant must be higher than
recommended or understood in the industry to reduce the quantity of
sticking in the ferric citrate tablets.
[0066] In certain variations, a combination of magnesium or calcium
stearate and sodium stearyl fumarate is used as a lubricant. In
further embodiments, the lubricant is a combination of calcium
stearate and sodium stearyl fumarate. In various embodiments, a
greater quantity of calcium stearate than is recommended in the art
can be used. As described in the Handbook of Pharmaceutical
Excipients fifth edition, the recommended quantity of calcium
stearate is a maximum of 1.0% w/w. In one embodiment, the quantity
of calcium stearate is equal to or greater than 2.0% w/w. In
another embodiment, the quantity of calcium stearate is equal to or
greater than 2.2% w/w. In another embodiment, the quantity of
calcium stearate is equal to or greater than 2.4% w/w.
[0067] Likewise, in various embodiments, a greater quantity of
sodium stearyl fumarate than the recommended 0.5-2.0% w/w
concentration can be used. In one embodiment, the quantity of
sodium stearyl fumarate is greater than or equal to 2.1% w/w. In
another embodiment, the quantity of sodium stearyl fumarate is
greater than or equal to 2.2% w/w. In another embodiment, the
quantity of sodium stearyl fumarate is greater than or equal to
2.3% w/w. In another embodiment, the quantity of sodium stearyl
fumarate is greater than or equal to 2.4% w/w. In another
embodiment, the quantity of sodium stearyl fumarate is greater than
or equal to 2.5% w/w. In another embodiment, the quantity of sodium
stearyl fumarate is greater than or equal to 2.6% w/w. In another
embodiment, the quantity of sodium stearyl fumarate is greater than
or equal to 2.7% w/w.
[0068] Post-Tableting Drying
[0069] A drying step can be performed after tableting. In the
absence of drying the tablet after tableting, it was discovered
that the dissolution rate of tablets increased over time. Drying
maintained the immediate release characteristics of the ferric
citrate tablets as disclosed herein. Without being limited to a
specific mechanism or mode of action, it is believed that granule
size increases due to the presence of residual water, and the
drying step maintains the large surface area per unit weight of the
original granules.
[0070] In one embodiment, the final granular water content as
measured by LOD % is less than 20%. In another embodiment, the
final granular water content as measured by LOD % is less than 19%.
In another embodiment, the final granular water content as measured
by LOD % is less than 18%. In another embodiment, the final
granular water content as measured by LOD % is less than 17%. In
another embodiment, the final granular water content as measured by
LOD % is less than 16%. In another embodiment, the final granular
water content as measured by LOD % is less than 15%. In another
embodiment, the final granular water content as measured by LOD %
is less than 14%. In another embodiment, the final granular water
content as measured by LOD % is less than 13%. In another
embodiment, the final granular water content as measured by LOD %
is less than 12%. In another embodiment, the final granular water
content as measured by LOD % is less than 11%. In another
embodiment, the final granular water content as measured by LOD %
is less than 10%. In another embodiment, the final granular water
content as measured by LOD % is less than 9%. In another
embodiment, the final granular water content as measured by LOD %
is less than 8%. In another embodiment, the final granular water
content as measured by LOD % is less than 7%. In another
embodiment, the final granular water content as measured by LOD %
is less than 6%. In another embodiment, the final granular water
content as measured by LOD % is less than 5%.
EXAMPLES
[0071] The following examples describe the preparation and
properties of various dosage forms and methods described herein. It
will be apparent to those skilled in the art that many
modifications, both to materials and methods, can be practiced
without departing from the scope of the disclosure.
Example 1
[0072] The following exemplary formulations and formulation
techniques for ferric citrate provide data showing characteristics
for the formulations or tablets, including data such as
dissolution, disintegration, and friability.
[0073] The sources for some of the materials included: ferric
citrate from Biovectra; silicified microcrystalline cellulose
(Prosolv SMCC 50 and Prosolv SMCC HD90 which is composed of
microcrystalline cellulose, NF and colloidal silicon dioxide, NF)
from JRS Pharma; pregelatinized starch, NF (Starch 1500) from
Colorcon; Povidone, NF (Plasdone K-29/32) from ISP; hydroxypropyl
cellulose, NF (Klucel EF) from Hercules; croscarmellose sodium, NF
(Ac-Di-Sol SD-711) from FMC Biopolymer; and magnesium stearate, NF
from Mallinckrodt.
[0074] The equipment used for the formulations included: FLM1 fluid
bed from Vector Corporation of Marion, Iowa; Comil conical mill
from Quadro Engineering of Millburn, N.J.; GMX high shear
granulator 4 L bowl from Vector Corporation of Marion, Iowa; 2 qt
v-blender from Patterson Kelley of East Stroudsburg, Pa.; XL 100
Pro tablet press from Korsch of South Easton, Mass.; capsule-shaped
tooling from Elizabeth Carbide of Lexington, N.C.; and Sonic sifter
separator from Advantech Manufacturing of New Berlin, Wis.
[0075] The equipment used for the analytical testing of the
formulations included: 8M Tablet Tester (hardness tester) from Dr.
Schleuniger of Manchester, N.H.; Friabilator from VanKel of Palo
Alto, Calif.; Flodex from Hanson Research of Chatsworth, Calif.;
Bathless Disintegration System, Model 3106 and Bathless Dissolution
System, Evolution 6100 from Distek of North Brunswick, N.J.; and
Model 8453 Uv-Vis from Agilent of Santa Clara, Calif.
[0076] High Shear Granulation
[0077] A series of experiments were conducted to determine the
ability to use a high shear granulator to make a tablet blend
having suitable characteristics. Formulations 1-3 are shown below
in Tables 1-3.
TABLE-US-00001 TABLE 1 (Formulation 1) Component mg/tablet % w/w
Milled Ferric Citrate 1190.3 75.0 Silicified microcrystalline 238.1
15.0 cellulose (Prosolv SMCC 50) Croscarmellose sodium 47.6 3.0
Hydroxypropyl cellulose 95.2 6.0 Magnesium stearate 15.9 1.0 Total
1587.0 100.0
TABLE-US-00002 TABLE 2 (Formulation 2) Component mg/tablet % w/w
Milled Ferric Citrate 1190.4 60.0 Silicified microcrystalline 595.2
30.0 cellulose (Prosolv SMCC 50) Croscarmellose sodium 59.5 3.0
Hydroxypropyl cellulose 119.0 6.0 Magnesium stearate 19.8 1.0 Total
1984.0 100.0
TABLE-US-00003 TABLE 3 (Formulation 3) Component mg/tablet % w/w
Milled Ferric Citrate 1190.3 69.0 Silicified microcrystalline 258.8
15.0 cellulose (Prosolv SMCC 50) Croscarmellose sodium 86.3 5.0
Hydroxypropyl cellulose 172.5 10.0 Magnesium stearate 17.3 1.0
Total 1725.0 100.0
[0078] The manufacturing procedure for the Formulations 1-3 were as
follows.
[0079] Milled ferric citrate, hydroxypropyl cellulose, silicified
microcrystalline cellulose, and croscarmellose sodium were mixed
for 2 minutes at 500 rpm in a GMX high shear granulator 4 L bowl.
Deionized water was added at an approximate rate of 18 g/min over
10 minutes, while mixing at a rate of 900 rpm with a chopper speed
of 1500 rpm. The final (peak) moisture content was measured to be
24.3%, 23.8%, and 24.4%, respectively. The granules were dried in a
FLM1 fluid bed for 5-8 minutes at an inlet temperature of
65.degree. C. The moisture content after drying was measured to be
14.3%, 15.5%, and 15.9%, respectively. The granules were screened
through a 16 mesh hand-screen, then through a 25 mesh hand screen
to remove over-sized granules and clumps. The magnesium stearate
was screened through a 25 mesh hand-screen. Granules and magnesium
stearate were blended for 2 minutes in a 2 quart v-blender.
Tableting was performed on a Korsch tablet press with capsule
shaped tooling.
[0080] It was found that the resulting tablet blends demonstrated
poor flow through the hopper due to the irregular particle shape of
the granules. Nonetheless, excellent tablets were able to be made
using the tableting equipment.
Example 2
[0081] Another series of experiments were conducted to determine
whether a tablet could be formulated using a fluid bed granulation
process:
TABLE-US-00004 TABLE 4 (Formulations 4 and 5) Component mg/tablet %
w/w Milled Ferric Citrate 1190.7 90.0 Pregelatinized starch 119.1
9.0 Magnesium stearate 13.2 1.0 Total 1323.0 100.0
[0082] Manufacturing Procedure for Formulations 4 and 5 depicted in
Table 4 are provided below as follows:
[0083] Milled ferric citrate was added to a FLM1 fluid bed
granulator. For Formulation 4, pregelatinized starch was added as a
10% w/w solution at a spray rate that increased from 24 g/min to 52
g/min over the duration of the run. [Inlet Temp=64-77.degree. C.;
Product Temp=25-35.degree. C.; Process Air=29-35 CFM]. The final
(peak) moisture content was measured to be 32.5%.
[0084] For Formulation 5, pregelatinized starch was added as a 10%
w/w solution at an average spray rate of 40.8 g/min. [Inlet
Temp=69-75.degree. C.; Product Temp=25-35.degree. C.; Process
Air=24-38 CFM]. The final (peak) moisture content was measured to
be 3.0%.
[0085] The granules were dried for 7-10 minutes at an inlet
temperature of 65.degree. C. The moisture content after drying was
measured to be 15.5% and 16.7%. Granules were milled through a
Comil equipped with a 45R screen and square impeller at 1500 rpm.
The magnesium stearate was screened through a 25 mesh hand-screen.
Granules and magnesium stearate were blended for two minutes in a
two quart V-blended. Tableting was performed on a Korsch tablet
press with capsule shaped tooling.
[0086] The primary difference between the tablets of Formulations 4
and 5 was the disintegration time. The tablets of Formulation 5 had
a slower disintegration time than the tablets of Formulation 4.
These prototypes had no flow problems during tableting.
[0087] The powder properties of Formulations 1-5 were characterized
as shown in Tables 5 and 6. All blends have excellent flow
properties as measured by the Flodex.
TABLE-US-00005 TABLE 5 Powder Characterization of High Shear Blends
Formulation Formulation Formulation Measurement 1 2 3 Bulk density
0.772 g/mL 0.618 g/mL 0.679 g/mL Flodex 4 5 10
TABLE-US-00006 TABLE 6 Powder Characterization of Fluid Bed Blends
Measurement Formulation 4 Formulation 5 Bulk density 0.647 g/mL
0.578 g/mL Flodex 4 4
[0088] Experimental formulations of Formulations 1 and 5 were
examined by Scanning Electron Microscopy (SEM) and both samples
have a similar particle size range. While the particles of
Formulation 1 appeared to have a bimodal distribution, both samples
have distinct particle morphologies. Formulation 1, which was
prepared by high shear granulation, has more sharp, oblong
particles. Formulation 5, prepared by fluid bed granulation, has
more soft, round particles. This difference is believed to have an
impact on the flow properties observed during tableting.
[0089] The tablet properties of Formulations 1-5 were characterized
as shown in Table 7 and Table 8. Compaction profiles were made of
each formulation, graphically presented in FIG. 1 (hardness), FIG.
2 (friability), and FIG. 3 (disintegration). Characterization data
is presented only of the tablets prepared at the highest compaction
force. Compression force is measured in kilo Newtons. Dissolution
results are graphically presented in FIG. 4 for Formulations 1 and
3-5.
[0090] For the hardness testing, the tablets were tested according
to USP <1217> for hardness/breaking strength. For the
friability testing, the tablets were tested following USP
<1216> for friability. For the disintegration testing, six
tablets were tested using a disintegration apparatus in deionized
water at 37.degree. C. For the dissolution testing, six tablets
were tested for dissolution properties according to the conditions
listed below. Tablet dissolution results were scaled to report 100%
dissolution as a 1000 mg dose, correcting for actual average tablet
weight, as needed.
[0091] Dissolution Conditions:
[0092] Dissolution Instrument: Distek Evolution 6100
[0093] Medium: pH 4.0 McIlvaine buffer
[0094] Apparatus USP: Apparatus II (paddle method); 100 rpm
[0095] Temperature: 37.degree. C..+-.0.5.degree. C.
[0096] Time: Samples taken at 5, 15, 30, and 60 minutes
[0097] UV-Vis Instrument: Agilent 8453 UV-Vis; 360 nm with 600 nm
background correction.
TABLE-US-00007 TABLE 7 Characterization of High Shear Experiments
(Formulations 1-3) Formulation Formulation Formulation Measurement
1 2 3 Weight Average 1580.8 mg Average 1485.6 mg Average 1518.4 mg
variation (0.5% RSD) (0.4% RSD) (0.7% RSD) Thickness Average 8.59
mm Average 8.37 mm Average 8.69 mm (0.2% RSD) (0.2% RSD) (0.4% RSD)
Hardness 18.1 kP 19.5 kP 21.5 kP (2.6% RSD) (2.3% RSD) (3.8% RSD)
Friability 0.19% 0.22% 0.26% Disintegration Average 5.8 Average
19.8 Average 3.0 minutes minutes minutes Dissolution 48.2% in 60 --
49.7% in 60 minutes minutes
TABLE-US-00008 TABLE 8 Tablet Characterization of Fluid Bed
Experiments (Examples 4 and 5) Measurement Formulation 4
Formulation 5 Weight variation Average 1286.5 mg Average 1313.2 mg
(0.3% RSD) (0.4% RSD) Thickness Average 7.18 mm Average 7.24 mm
(0.2% RSD) (0.2% RSD) Hardness Average 19.3 kP 20.5 kP (3.2% RSD)
(7.4% RSD) Friability 0.20% 0.23% Disintegration Average 7.7
minutes Average 36.3 minutes Dissolution 50.4% in 60 minutes 42.5%
in 60 minutes
[0098] For the high shear prototypes (Formulations 1-3)
incorporation of increased silicified microcrystalline cellulose
(Formulation 1 and Formulation 2) improved compactibility, as shown
by reduced compression forces required to achieve equivalent
hardness. Also, incorporation of increased hydroxypropyl cellulose
(Formulations 1, 2, and 3) improved compactibility, as shown by
reduced compression forces required to achieve equivalent
hardness.
Example 4
[0099] Additional development was conducted to achieve a balance
between dissolution profile and acceptable tablet properties. The
fluid bed granulation spray rate was varied step-wise using
pregelatinized starch, which showed that in-process moisture
content plays a role in dissolution profile and tablet
properties.
[0100] Fluid Bed Granulation with Starch
[0101] Batches of Formulations 6-11 shown in Tables 9 and 10 were
prepared using pregelatinized starch with target batch sizes of 1.0
kg.
TABLE-US-00009 TABLE 9 Formulation Formulations 6-8 Component
mg/tablet % w/w Milled Ferric Citrate 1190.7 90.0 Pregelatinized
starch 119.1 9.0 Magnesium stearate 13.2 1.0 Total 1323.0 100.0
TABLE-US-00010 TABLE 10 Formulation Formulations 9-11 Component
mg/tablet % w/w Milled Ferric Citrate 1190.7 80.9 Pregelatinized
starch 119.1 8.1 Silicified microcrystalline cellulose 147.2 10.0
Magnesium stearate 13.2 1.0 Total 1470.2 100.0
[0102] Formulations 6-11 were manufactured as follows:
[0103] Milled Ferric Citrate was added to a FLM1 fluid bed
granulator. Pregelatinized starch was added as a 10% w/w solution
using the granulation and drying parameters in Table 11. All
batches were dried at an inlet temperature of 65.degree. C.
TABLE-US-00011 TABLE 11 Granulation Parameters Formulation
Formulations Formulations Parameter 6 and 9 7 and 10 8 and 11 Spray
rate 24.0 g/min 32.5 g/min 37.5 g/min Inlet temp 69-79.degree. C.
72-75.degree. C. 69-76.degree. C. Product temp 26-35.degree. C.
26-36.degree. C. 26-35.degree. C. Process air 31-36 CFM 32-38 CFM
36-39 CFM Final (peak) moisture 17.3% 23.4% 25.7% Moisture after
drying 14.8% 16.1% 17.5% Drying time 2 minutes 5 minutes 7
minutes
[0104] Granules from Formulations 6, 7, 9 and 10 were screened
through a 20 mesh hand-screen. Granules from Formulations 8 and 11
were milled through a Comil equipped with a 45R screen and square
impeller at 1500 rpm, then screened through a 20 mesh
hand-screen.
[0105] Two blends were prepared from each granulation. In the first
blend, the magnesium stearate was screened through a 25 mesh
hand-screen. Granules and magnesium stearate were blended for two
minutes in a two quart V-blender. In the second blend, the
magnesium stearate was screened through a 25 mesh hand-screen.
Granules, silicified microcrystalline cellulose, and magnesium
stearate were blended for two minutes in a two quart V-blender.
[0106] Tableting was performed on a Korsch tablet press with
capsule shaped tooling on several of the prepared blends.
[0107] The resulting tablets of Formulations 6 and 9 had flow
properties with Hausner ratio values equal to or less than 1.25
and/or Carr index values equal to or less than 25. In various
embodiments, the Hauser ratio is equal to or less than 1.20. In
further embodiments, the Hauser ratio is equal to or less than
1.20. In various embodiments, the Carr index is less than 25. In
further embodiments, the Carr index is equal to or less than
20.
[0108] Excellent flow: Hausner ration values about or less than
1.20 and Carr index values less than 20) but showed evidence that
additional lubrication was needed to achieve better tableting
results. The resulting tablets of Formulations 7, 8, 10 and 11 had
excellent flow properties and made successful tablets.
[0109] The powder properties of Formulations 6-11 were
characterized as shown in Tables 12 and 13. Formulations 7, 8, 10
and 11 have flow properties with Hauser ratios equal to or less
than 1.20 and Carr index values less than 20 as measured by the
Flodex, presumably due to the higher spray rates of those
experiments. The bulk density of the starch granulation experiments
increased as the spray rate increased.
TABLE-US-00012 TABLE 12 Powder Characterization of Fluid Bed
Experiments Formulations Formulations Formulations Measurement 6
and 9 7 and 10 8 and 11 Bulk density 0.475 g/mL 0.531 g/mL 0.698
g/mL Flodex 7 4 4
[0110] The tablet properties of Formulations 6-8 and 11 were
characterized as shown in Table 13 and 14. Compaction profiles were
made for each formulation and are graphically presented in FIG. 5
(hardness), FIG. 6 (friability) and FIG. 7 (disintegration).
Characterization data is presented only of the tablets prepared at
the highest compaction force. Dissolution results are graphically
presented in FIG. 8 for Formulations 6-8 and 11.
TABLE-US-00013 TABLE 13 Tablet Characterization of High Shear
Formulations 6 and 7 Measurement Formulation 6 Formulation 7 Weight
variation Average 1126.9 mg (0.4% RSD) Average 1272.8 mg (0.4% RSD)
Thickness Average 7.74 mm (0.2% RSD) Average 8.00 mm (0.5% RSD)
Hardness Average 11.2 kP (28.7% RSD) 27.2 kP (8.9% RSD) Friability
2.23% 0.36% Disintegration Average 1.8 minutes Average 3.9 minutes
Dissolution 99.9% in 60 minutes 95.7% in 60 minutes
TABLE-US-00014 TABLE 14 Tablet Characterization of Fluid Bed
Formulations 8 and 11 Measurement Formulation 8 Formulation 11
Weight variation Average 1332.0 mg (0.3% RSD) Average 1497.7 mg
(0.3% RSD) Thickness Average 7.94 mm (0.1% RSD) Average 8.72 mm
(0.1% RSD) Hardness Average 21.1 kP (2.8% RSD) 26.1 kP (2.9% RSD)
Friability 0.28% 0.15% Disintegration Average 11.7 minutes Average
8.3 minutes Dissolution 55.8% in 60 minutes 65.6% in 60 minutes
[0111] Milled Ferric Citrate and croscarmellose sodium were added
to a FLM1 fluid bed. Povidone was added as a 30% w/w solution
(Formulation 12) and 20% w/w solution (Formulation 13) using the
granulation and drying parameters in Table 15 to make granules. No
drying was required.
TABLE-US-00015 TABLE 15 Granulation Parameters Parameter
Formulation 12 Formulation 13 Spray rate 22.9 g/min 30.0 g/min
Inlet temp 55-60.degree. C. 52-58.degree. C. Product temp
31-37.degree. C. 22-30.degree. C. Process air 31-36 CFM 35-38 CFM
Final (peak) moisture 13.0% 17.3%
[0112] Granules were screened through a 20 mesh hand-screen. The
magnesium stearate was screened through a 25 mesh hand-screen.
Granules and magnesium stearate were blended for two minutes in a
two quart V-blender.
[0113] Tableting was performed on a Korsch tablet press. During the
tableting process, there was excessive sticking to the tooling.
This sticking was believed to be addressable by use of different
tooling or by varying the tableting parameters.
Example 6
[0114] Additional examples were formulated and analyzed. A summary
of the results are provided below in Tables 16 and 17. Table 16
provides a summary of results for Formulations 14-20 using direct
compression of the formulations. Table 17 provides a summary of
results for Formulations 21-29 using fluid bed granulation. These
various formulations showed a variety of ranges of properties that
could be useful depending upon the application, e.g., immediate
release, extended release, and delayed release, with a minor amount
of additional experimentation required for some of the formulations
to ensure that suitable tablets are formed.
TABLE-US-00016 TABLE 16 Qualitative Results for Direct Compression
Formulations Experiment Dose Reference Target Formulation Summary
Results and Observations Formulation 667 mg 91.9% Ferric Citrate,
Tablets had some lamination, 14 7.3% Prosolv SMCC 50, achieved 12.5
kP average 0.8% Magnesium Stearate hardness Formulation 667 mg
91.9% Ferric Citrate, Friability equal to or less than 15 7.3%
Prosolv HD 90, 1.0% w/w. 0.8% Magnesium Stearate Formulation 667 mg
87.0% Ferric Citrate, Friability equal to or less than 16 7.3%
Prosolv SMCC 50, 1.0% w/w. 4.9% Povidone K-29/32, 0.8% Magnesium
Stearate Formulation 500 mg 90.7% Ferric Citrate, Tablets show
capping and 17 8.5% Prosolv HD 90, lamination addressable with 0.8%
Magnesium Stearate additional binder or varying the tableting
parameters Formulation 500 mg 90.7% Ferric Citrate, Tablets show
capping and 18 8.0% Prosolv HD 90, lamination addressable with 0.5%
Povidone K-29/32, additional binder or varying the 0.8% Magnesium
Stearate tableting parameters; long disintegration times
Formulation 500 mg 88.0% Ferric Citrate, Tablets show capping and
19 7.0% Avicel PH 200, lamination addressable with 2.7% Povidone
K-29/32, additional binder or varying the 1.5% Crospovidone XL,
tableting parameters; 0.8% Magnesium Stearate disintegration time
reduced to 1-3 minutes suitable for immediate release applications
Formulation 500 mg 87.0% Ferric Citrate, Tablets show reduced
lamination 20 7.0% Avicel PH 200, that was addressable with 3.7%
Povidone K-29/32, additional binder or varying the 1.5%
Crospovidone XL, tableting parameters, 0.8% Magnesium Stearate
disintegration time 3-5 minutes suitable for immediate release
applications
TABLE-US-00017 TABLE 17 Qualitative Results for Fluid Bed
Granulation Formulations Experiment Dose Reference Target
Formulation Summary Results and Observations Formulation 500 mg
90.0% Ferric Citrate, Friability equal to or less than 21 2.0%
Povidone K-29/32, 1.0% w/w. 2.0% Starch 1500, 5.2% Avicel PH 102,
0.8% Magnesium Stearate Formulation 500 mg 90.0% Ferric Citrate,
Acceptable tablet properties with 22 4.0% Starch 1500, additional
development work 5.2% Avicel PH 102, needed for tablet integrity
0.8% Magnesium Stearate Formulation 500 mg 90.0% Ferric Citrate,
Tablets have disintegration to be 23 9.0% Starch 1500, more than 15
minutes. 1.0% Magnesium Stearate Formulation 500 mg 90.0% Ferric
Citrate, Tablets have disintegration to be 24 4.0% Starch 1500,
more than 15 minutes. 5.2% Avicel PH 102, 0.8% Magnesium Stearate
Formulation 500 mg 80.0% Ferric Citrate, Tablets have
disintegration to be 25 8.0% Starch 1500, more than 15 minutes.
11.0% Avicel PH 200, 1.0% Magnesium Stearate Formulation 500 mg
90.0% Ferric Citrate, Tablets have disintegration to be 26 9.0%
Starch 1500, more than 15 minutes. 1.0% Magnesium Stearate
Formulation 500 mg 85.0% Ferric Citrate, Tablets have
disintegration to be 27 8.5% Starch 1500, more than 15 minutes.
5.5% Avicel PH 200, 1.0% Magnesium Stearate Formulation 1000 mg
84.9% Ferric Citrate, Granulation very dense 28 5.6% Starch 1500,
8.6% Avicel PH 200, 1.0% Magnesium Stearate Formulation 1000 mg
89.5% Ferric Citrate, Acceptable tablet properties with 29 5.9%
Starch 1500, tableting and coating successful 3.6% Avicel PH 200,
1.0% Magnesium Stearate
Example 7
[0115] Tables 18a and 18b provide Formulation 29 and 30 for an
exemplary ferric citrate drug product.
TABLE-US-00018 TABLE 18a Formulation for a Ferric Citrate Drug
Product Theoretical Material Description kg/Batch % w/w Ferric
Citrate 14.89 87.6 Pregelatinized Starch 1.70 10.0 Calcium Stearate
0.406 2.4 Purified Water 15.30* N/A** Core Tablet Total 17.00 100.0
Opadry Purple 03K100000 0.51 15.0 Purified Water 2.89* 85.0**
Coated Tablet Total 17.5 100.0 *Purified water is removed during
the drying phase.
TABLE-US-00019 TABLE 18b Formulation for a Ferric Citrate Drug
Product Theoretical Material Description Kg/Batch % w/w Ferric
Citrate 14.87 85.0 Silicified Microcrystalline 0.70 4.0 Cellulose
Pregelatinized Starch 1.58 9.0 Calcium Stearate 0.35 2.0 Purified
Water 14.18 N/A* Core Tablet Total 17.5 100.0 Opadry Purple
03K100000 0.51* 15.0 Purified Water 2.89* 85.0** Coated Tablet
Total 18.0 100.0
[0116] Table 19 provides a proposed ferric citrate drug product
formulation that can be used in the manufacturing process described
below.
TABLE-US-00020 TABLE 19 Formulation 31 Material Theoretical % w/w
to Core % w/w Coated Description 100 kg/Lot Tablet Tablet Ferric
Citrate 80.0-90.0 80.0-90.0 76.2-88.2 Pregelatinized 8.0-15.0
8.0-15.0 7.6-14.7 Starch Calcium Stearate 2.0-3.0 2.0-3.0 1.9-2.9
Purified Water N/A* N/A* N/A* Core Tablet Total 100.0 100.0 N/A*
Opadry Purple 5.3 15.0 2.0-5.0 03K100000 Purified Water 30.0* 85.0*
N/A* Coated Tablet 35.3 100.0 100.0 Total *Purified water is
removed
Example 8
[0117] The drug product tablet was produced using fluid bed
granulation of the screened API with a binder suspension of
pregelatinized starch, targeting for a moisture content after
granulation of approximately 13-20%. The granulated active was
subsequently blended with screened calcium stearate and the mix
compressed to form a tablet core. The tablet was robust with
friability equal to or less than 1.0% w/w, hardness from 8-20 kP,
disintegration equal to or less than 15 min, and compression force
about 3.5-5.0 kN, with a main force 5-20 kN. It will be recognized
that various embodiments are within the ranges of one or more of
each of these parameters.
[0118] The weight of individual tablets can depend upon the final
dosage to be produced; e.g., 125 mg, 250 mg, 500 mg, 667 mg, 750 mg
and 1,000 mg of Ferric citrate. The process is capable of
consistently producing tablets within a specification of .+-.5% of
target. The tablet thickness and hardness meet the specified
acceptance criteria. The tablets are coated to a target weight gain
of approximately 2% to 5% using an Opadry suspension or equivalent
in a perforated pan coater.
[0119] The production results demonstrate the selected formulation
and process is capable of producing robust tablets meeting the
specified criteria. First, ferric citrate was passed through a
screening mill. A granulation drug binder suspension was then
prepared by adding purified water to a stainless steel mixing
kettle, then adding pregelatinized starch to the purified water and
mix. Granulated particles were formed by screening ferric citrate
through a fluid granulator. The pregelatinized starch binder
suspension was sprayed into the fluidized product bed. At the
completion of binder addition the granulation is dried.
[0120] The dried granules were charged into a diffusion mixer.
Calcium stearate was screened and added to the granulation in the
diffusion mixer. The granules and lubricant were mixed.
[0121] The lubricated granules were compressed into tablets.
Tablets were collected in intermediate bulk containers. An aqueous
film coating suspension was prepared in a stainless steel kettle
and mixer. The tablets were charged into a fully perforated pan
coater, and the coating suspension was sprayed onto the cascading
product bed. Upon completion of the spraying step the tablets were
dried. Film coated tablets were discharged into intermediate bulk
containers. The film coated tablets were packaged in HPDE bottles
with desiccant and child resistant foil induction seal cap.
Example 9
[0122] Ferric citrate tablets were formulated as described above.
Tablet formulations 32 and 33 are depicted in Tables 20 and 21.
TABLE-US-00021 TABLE 20 Formulation 32 % w/w Material Target
Theoretical % w/w Coated Description kg/Batch 100 kg/Lot Individual
Tablet Ferric Citrate 14.9 80.0-90.0 80.0-90.0 76.2-88.2
Pregelatinized 1.7 8.0-15.0 8.0-15.0 7.6-14.7 Starch Calcium
Stearate 0.4 1.0-3.0 1.0-3.0 0.9-2.9 (1) OR - Sodium 0.4 2.0-3.0
2.0-3.0 1.9-2.9 Stearyl Fumarate (1) Purified Water 15.3*
72.0-135.0* * * Core Tablet Total 17.0 100.0 100.0 N/A* Opadry
Purple 0.9 5.3 15.0 2.0-5.0 Purified Water 5.1* 30.0* 85.0* N/A*
Coated Tablet 17.5 to 17.9 35.3 100.0 100.0 Total (1)-use either
calcium stearate or sodium stearyl fumarate as lubricant *Purified
water is removed
TABLE-US-00022 TABLE 21 Formulation 32 % w/w Material Target
Theoretical % w/w Coated Description kg/Batch 100 kg/Lot Individual
Tablet Ferric Citrate 14.9 80.0-90.0 80.0-90.0 76.2-88.2
Pregelatinized 1.6 8.0-12.0 8.0-12.0 7.6-11.5 Starch Silicified 0.7
3.0-5.0 3.0-5.0 2.5-4.5 Microcrystalline Cellulose Calcium Stearate
0.4 1.0-3.0 1.0-3.0 0.9-2.9 (1) OR - Sodium 0.4 2.0-3.0 2.0-3.0
1.9-2.9 Stearyl Fumarate (1) Purified Water 15.3* 72.0-135.0* * *
Core Tablet Total 17.6 to 18.0 100.0 100.0 N/A* Opadry Purple 0.9
5.3 15.0 2.0-5.0 03K100000 Purified Water 5.1* 30.0* 85.0* N/A*
Coated Tablet 17.8 to 18.9 35.3 100.0 100.0 Total (1) use either
calcium stearate or sodium stearyl fumarate as lubricant *Purified
water is removed
Example 10
[0123] A ferric citrate tablet was made under conditions in which
granulation was conducted by allowing the LOD water % to increase
above 25%.
Pharmaceutical grade ferric citrate was added into a fluid bed
granulator. Pregelatinized starch binder suspension (Pregelatinized
starch+water) was sprayed into the fluidized product bed. The water
moisture level of the formulation was allowed to exceed 25% by LOD
(loss on dried method). In embodiments in which the moisture of the
formulation was brought to the level above 25% LOD at any point
resulted in a substantially lower surface area per gram of
particle.
[0124] Referring Table 22, the increase the moisture provided
during manufacturing increased above 20% at 120 minutes, increased
to 27.87% at 170 minutes.
TABLE-US-00023 TABLE 22 Granulation Operating Parameters Prod- Ex-
Pump Inlet Inlet uct Atom haust Rate Speed Air Temp Temp Air LOD
Temp Time (g/min) (rpm) (scfm) (.degree. C.) (.degree. C.) (psi)
(%) (.degree. C.) 0 -- -- 145 42 35.8 65.0 11.85 30.6 10 87.7 30
150 61.6 30.0 65.0 12.82 28.4 20 71.2 30 153 63.5 28.2 65.0 13.02
26.6 30 76.2 30 153 63.1 27.5 64.7 13.18 25.8 40 77.7 30 144 63
27.1 65.1 15.19 25.4 50 75.9 30 146 63.1 27.0 65.1 15.7.0 25.3 60
79.6 30 147 63.0 26.8 65.1 15.74 25.2 71 80.0 30 144 62.9 26.7 65.1
-- 25.1 80 83.4 33 149 63.0 26.7 65.1 17.31 25.1 90 90.5 33 151
63.0 26.5 65.1 18.49 25.0 100 90.4 33 152 63.0 26.5 65.1 18.64 24.9
110 90.5 33 153 63.0 26.4 65.1 18.99 24.8 120 90.5 33 150 63.0 26.4
65.1 22.89 24.8 130 90.4 33 144 63.0 26.3 65.1 22.47 24.8 141 91.1
33 153 63.0 26.3 65.1 24.25 24.7 150 90.2 33 152 63.0 26.2 65.1
25.41 24.7 160 91.8 33 153 62.9 26.2 65.0 26.03 24.7 170 89.6 33
154 63.0 26.2 65.1 27.89 24.7 180 90.7 33 149 63.0 26.2 65.1 27.47
24.7 190 -- -- 147 63.0 26.4 -- 26.76 24.7 200 -- -- 150 63.0 26.8
-- 25.00 25.0 210 -- -- 154 63.1 27.2 -- 22.37 25.1 220 -- -- 153
63.1 27.8 -- 21.32 25.2 230 -- -- 149 63.1 29.0 -- 18.68 25.7 240
-- -- 153 63.1 30.7 -- 17.55 26.5 Final 16.69 LOD
[0125] The measured surface area of two samples prepared using the
above formulation is depicted in Table 23. The surface areas of the
formulations were 0.12 m.sup.2/g and 0.20 m.sup.2/g.
TABLE-US-00024 TABLE 23 Sample 1 BET Sample 2 BET Sample Surface
Area (m.sup.2/g) Surface Area (m.sup.2/g) Pre- 27.99 32.34
granulation(API + ProSolv) PostGranulation 0.12 0.20
[0126] The mean surface area per unit mass ratios of the two
samples was 0.12 and 0.20 m.sup.2/g, respectively.
Example 11
[0127] A ferric citrate tablet was prepared by keeping granules at
an LOD % water concentration less than 25% during granulation.
[0128] Pharmaceutical grade ferric citrate was added into a fluid
bed granulator. Pregelatinized starch binder suspension
(Pregelatinized starch+water) was sprayed into the fluidized
product bed. With reference to Table 24, the moisture level of the
formulation was maintained at below 20% by LOD (loss on dried
method) at all times during the spraying process. The surface area
of the resulting formulation was greater than 10 square meters per
gram.
TABLE-US-00025 TABLE 24 Prod- Ex- Spray Pump Inlet Inlet uct Atom
haust Time Rate Speed Air Temp Temp Air Temp LOD (min) (g/min)
(rpm) (SCFM) (.degree. C.) (.degree. C.) (psi) (.degree. C.) (%) 0
-- -- 149 55.4 39.8 -- 44.5 12.05 10 86.1 31 153 70.3 36.0 65.0
39.6 12.44 20 88.2 31 152 70.1 32.0 64.9 35.4 13.01 30 87.9 31 146
69.8 30.0 65.1 36.6 13.38 40 90.1 31 153 70.0 28.9 64.8 30.6 13.80
50 85.2 31 151 70.0 28.6 65.1 29.8 14.36 60 87.5 31 144 70.0 28.2
65.1 28.9 15.03 70 89.0 31 153 72.5 28.1 65.1 28.4 16.49 80 87.0 31
145 75.9 28.4 65.1 28.3 16.34 90 88.7 31 153 78.5 28.9 65.1 28.5
17.25 100 94.0 31 149 80.3 29.2 64.9 28.5 17.43 110 82.5 31 153
80.2 29.2 65.1 28.4 19.60 120 78.3 25 152 79.9 30.0 64.9 28.9 19.08
130 66.4 25 153 79.9 29.2 64.9 28.4 19.24 141 66.3 25 152 79.8 29.8
65.1 28.6 19.29 150 66.1 25 153 80.2 29.7 64.9 28.7 18.44 160 65.7
25 152 80.1 29.6 65.1 28.5 18.43 170 66.1 25 153 80.1 30.0 65.1
28.8 18.85 181 57.7 25 152 79.9 29.4 64.8 28.4 -- 191 76.9 25 154
80.0 29.4 65.0 28.3 16.70 200 63.9 25 153 80.0 30.2 65.0 28.7 18.64
210 -- -- 150 74.6 31.0 -- 28.0 16.97 220 -- -- 150 80.7 37.1 --
31.7 14.95 Final 13.30 LOD=
[0129] The results showed a reduced surface area between the
pre-granulated and granulated materials (see the Table 25). The
results are depicted in Table 25, Sample 1. Table 25, samples 2 and
3 also show a surface area of over 10 m.sup.2/g, which corresponds
to rapid immediate release formulation characteristics as described
herein. The difference in granule particle size is nearly two
orders of magnitude over granules that were prepared with increased
water as measured by LOD %.
TABLE-US-00026 TABLE 25 Sample 1 BET Sample 2 BET Sample 3 BET
Surface Area Surface Area Surface Area Sample (m.sup.2/g)
(m.sup.2/g) (m.sup.2/g) Pre-granula- 28.87 28.87 28.87 tion(API +
ProSolv) PostGranulation 11.85 14.03 10.18 PTLReportNumber 19005
19005 19005
[0130] A significant increase in particle surface area
corresponding to a reduction in particle size. Tablets with higher
granular surface area faster dissolution rate when compared to
tablets prepared with a lower surface area per unit weight.
[0131] Calcium stearate and sodium stearyl fumarate were added as
lubricants. The quantity used in the formula are beyond the
quantities recommended in the art (e.g. Handbook of Pharmaceutical
Excipients fifth edition). 0.5% w/w of sodium stearyl fumarate 2.4%
w/w of calcium stearate was used.
Example 12
[0132] A ferric citrate tablet was produced for clinical study as
described above. The quantities of tablet components used are
depicted in Table 26.
TABLE-US-00027 TABLE 26 Material Description Target kg/Batch % w/w
Individual Ferric Citrate 14.89 87.6 Pregelatinized Starch 1.70
10.0 Calcium Stearate (1) 0.406 2.4 Purified Water 15.30 N/A Core
Tablet Total 17.00 100.0 Opadry Purple 0.51 15.0 Purified Water
2.89 85.0 Coated Tablet Total 17.5 100.0
Pregelatinized starch was sprayed into a chamber maintained at
inlet temperature and product temperature. The LOD % water at every
stage of preparation was maintained under 20%. The parameters used
during the formulation are disclosed in Table 27.
TABLE-US-00028 TABLE 27 Prod- Ex- Spray Pump Inlet Inlet uct Atom
haust Time Rate Speed Air Temp Temp Air Temp LOD (min) (g/min)
(rpm) (SCFM) (.degree. C.) (.degree. C.) (psi) (.degree. C.) (%) 0
-- 38 150 61.5 42.6 60 11.24 41.3 10 107.6 38 151 63.0 31.3 60 12.4
34.5 20 109.1 38 151 63.1 27.1 60 13.32 29.5 30 109.5 38 150 63.0
26.1 60 14.37 27.5 40 109.5 38 151 63.0 25.5 60 15.64 26.4 50 109.6
38 151 62.9 25.3 60 16.99 25.7 60 109.5 38 152 69.4 25.9 60 17.66
25.5 71 109.9 38 153 72.8 26.9 60 19.35 26.3 80 94.7 30 153 72.3
26.9 60 17.05 26.3 90 91.0 35 151 71.7 27 60 19.66 26.3 100 88.5 30
152 72.1 27.1 60 19.57 26.3 110 81.7 30 150 73.3 27.4 60 18.88 26.4
120 85.7 33 153 73.2 27.7 60 16.39 26.6 130 97.9 35 149 72.4 27.4
60 18.87 26.5 141 94.5 33 152 72.0 27.4 60 18.78 26.3 150 93.3 34
153 71.9 27.3 60 18.62 26.3 160 93.4 34 152 71.8 27.5 60 18.30 26.3
170 95.6 34 154 72.2 27.5 60 19.49 26.4 180 -- -- 151 71.9 29.5 --
16.71 26.8
The targeted peak moisture between 19-20% (LOD) was achieved with a
moisture content of 19.66% (LOD). Table 28 and Table 29 summarize
the physical properties after the granulation step and after the
tableting and drying steps.
TABLE-US-00029 TABLE 28 Granulation Characteristics ScreenSize %
Retained 35 (500 .mu.m) 0.0 45 (355 .mu.m) 1.3 60 (250 .mu.m) 11.1
80 (180 .mu.m) 16.2 120 (125 .mu.m) 19.4 170 (90 .mu.m) 16.0 230
(63 .mu.m) 16.3 Pan 18.8
TABLE-US-00030 TABLE 29 Final blend (post-tableting and drying)
characteristics BulkDensity (g/ml) 0.460 TappedDensity (g/ml) 0.566
HausnerRatio 1.23 CarrIndex 19
Table 30 and Table 31 summarize the final blend characteristics of
the formulations.
TABLE-US-00031 TABLE 30 Final Blend Characteristics ScreenSize %
Retained 35 (500 .mu.m) 0.0 45 (355 .mu.m) 0.8 60 (250 .mu.m) 10.8
80 (180 .mu.m) 16.6 120 (125 .mu.m) 20.3 170 (90 .mu.m) 17.2 230
(63 .mu.m) 15.6 Pan 17.0
TABLE-US-00032 TABLE 31 Test Results BulkDensity (g/ml) 0.436
TappedDensity (g/ml) 0.573 HausnerRatio 1.31 CarrIndex 24
TABLE-US-00033 TABLE 32 AttributeorSetting Start Middle End
PressMainForce (kN) 9.9 9.9 -- PressPreForce (kN) 3.5 4.0 --
PressSpeed (rpm) 28.69 28.69 -- Friability (%) 0.2 -- --
Disintegration (seconds) 88 95 105
TABLE-US-00034 TABLE 33 Characteristic Weight Thickness Hardness
Mean 1161 7.709 15.7 StandardDeviation 9.39 0.029 1.13
MinIndividual 1150 7.680 13.8 MaxIndividual 1186 7.800 18.0 RSD
0.81 0.38 7.20 Cpk 1.88 2.21 1.26
[0133] The compression data demonstrates that the subject
formulation and process were capable of producing a robust tablet
with rapid disintegration. The Cpk value for individual tablet
weight demonstrates the process was capable of consistently
producing tablets within a specification of .+-.5% of target. The
tablet thickness and tablet hardness met the specified acceptance
criteria.
Coating and Drying Operating Parameters:
[0134] The Opadry coating suspension was prepared to 15% solids
content by weight. The theoretical weight gain for the subject
batch was 3%. The film coating was a non-functional component used
for aesthetics purposes only and therefore the actual weight gain
was not critical to drug performance. The process sprayed to the
theoretical quantity of coating suspension and not to a specific
weight gain (an efficiency factor was not used). The average coated
tablet weight post drying 1110 mg. The operating parameters in
Table 34 were used during the coating process:
TABLE-US-00035 TABLE 34 Ex- Inlet Dew haust Spray Atom Pan Time
AirFlow Temp Point Temp Rate Air Speed (min.) (cfm) (.degree. C.)
(.degree. C.) (.degree. C.) (g/min) (psi) (rpm) 0 308 55.0 4.9 33.2
45 37 10 15 317 46.0 5.6 36.4 48 37 10 30 307 45.1 6.3 37.3 44 37
10 45 309 50.4 7.6 34.6 40 37 10 60 307 44.4 7.6 36.7 51 37 10 75
310 52.9 7.5 37.3 53 37 10
The operating parameters in Table 35 were used during the final
tablet drying process:
TABLE-US-00036 TABLE 35 Time Air Flow Inlet Temp DewPoint Exhaust
Temp % Water (min) (cfm) (.degree. C.) (.degree. C.) (.degree. C.)
(LOD) 0 503 70.2 7.3 50.6 13.19 15 504 69.7 7.2 63.3 11.93 30 494
69.6 7.2 65.4 11.33 45 502 69.6 7.0 66.3 11.14 60 500 70.4 6.8 67.0
10.14 75 502 80.1 7.0 73.0 9.73 90 501 80.2 7.0 74.5 9.59 105 505
79.7 6.8 75.4 8.96 120 509 81.1 6.8 75.7 8.78 135 510 81.2 6.6 76.2
8.21 150 505 81.1 6.7 76.5 7.88
[0135] The dissolution profiles demonstrate that higher moisture
levels in the tablet can reduce the dissolution rate over time.
Tablets with high moisture content exposed to high temperature
experienced accelerated reductions in dissolution rate. The post
dried tablet, which had an end moisture content of 8.84% (LOD), did
not experience the same reduction in dissolution rate. The tablets
containing high moisture level and calcium stearate experienced the
greatest reduction in dissolution rate.
[0136] The core and coated tablets containing calcium stearate had
slightly higher moisture contents (.about.15% LOD) when compared to
the core tablets containing sodium stearyl fumarate (.about.14%
LOD). Without wishing to be held to a particular theory or mode of
action, this could be contributing to the difference in the
observed dissolution rates. The final moisture content of the
tablet and moisture in the tablet during manufacture appear to
contribute to the immediate release characteristics and long term
stability of the tablet.
[0137] The one month stability profile of pre-dried and post dried
tablets stability were measured. The stability included both
25.degree. C./60% RH and 40.degree. C./75% RH conditions. All
samples were placed into HDPE bottles (0.025'' wall thickness) with
a foil induction seal cap, and a small portion of the study
included bottles with desiccants. The following charts summarize
the informal stability data.
[0138] With reference to FIG. 9, the immediate dissolution rate
(greater than 80% at 60 minutes after administration) of tablets
exposed to the post-dry process was maintained. The dissolution
rate reduced dramatically after one week at in the absence of the
post-dry process.
Example 13: Clinical Study of Ferric Citrate Dosage Forms
[0139] A protocol for performing clinical studies of a ferric
citrate drug formulation as described above is provided as
follows.
[0140] The protocol includes a 6-Week Feasibility Trial of a New
Formulation of KRX-0502 (Ferric Citrate) in Patients with End-Stage
Renal Disease (ESRD). The objective of the study is to determine
the potential efficacy as a dietary phosphate binder and
tolerability of KRX-0502 (ferric citrate) in controlling and
managing serum phosphorus levels in patients with end-stage renal
disease (ESRD) and monitoring the change in serum phosphorus from
baseline to end of treatment after a four week treatment
period.
[0141] The study design includes conducting the study of the drug
in patients with ESRD on thrice weekly hemodialysis. Approximately
24 patients (twelve diabetic and twelve non-diabetic patients) will
be initiated on study drug over two to three weeks.
[0142] The study consists of five periods: Screening, Washout,
Study Drug Initiation, Treatment, and Final Visit. The two-week
washout period is immediately followed by a six-week treatment
period. The duration of the clinical trial is approximately three
to four months with approximately two to three weeks being
allocated for patient screening, washout, and initiation of the
study drug.
[0143] The study population includes all ESRD patients on thrice
weekly hemodialysis for at least three months prior to the Study
Drug Initiation Visit (Visit 3) who are currently taking at least
three tablets/capsules per day of calcium acetate, calcium
carbonate, lanthanum carbonate or sevelamer (hydrochloride or
carbonate) or any combination of these agents will be eligible for
enrollment. Approximately twelve patients will be diabetic and
twelve patients will be non-diabetic. Approximately 24 to 48
patients will be screened to initiate approximately 24 patients on
study drug. All patients will be recruited from 2-4 sites.
[0144] The study for the drug administration includes initiating
approximately 24 patients on KRX-0502 (ferric citrate) following a
two week washout period from their current phosphate binder and
monitoring the serum phosphorus level during the study. The target
level of serum phosphorus is approximately 3.5 to 5.5 mg/dL. The
serum phosphorus levels will be checked weekly during the washout
period and during the visits 4, 5, 6, and at the Final Visit (Visit
7) of the treatment period
[0145] The KRX-0502 dosage is determined by initiating all patients
on the study drug with a fixed dosage of 6 tablets per day with
each tablet of ferric citrate containing 210 mg of ferric iron as
ferric citrate (approximately 720 mg of ferric iron as ferric
citrate) and titrating the blood samples of the patients at Visits
4, 5, and 6 as follows:
[0146] For a serum phosphorus level from 3.5-5.5 mgs/dL of the
blood, no action is required, for a rise to >5.6-6.9 mgm/dL, the
drug dosage is increased by one tablet per day and for a rise to
6.9 mg/d, the dosage is increased to 3 tablets per day to a maximum
of 12 tablets/day.
[0147] Patients take the study drug orally with meals or snacks or
within one hour after their meals or snacks. Patients are
instructed not to take the study drug if greater than one hour has
passed since the ingestion of their meals or snacks. Some patients
can require a different distribution in tablets in a given day due
to snacks or missed meals. For example, if the patient is receiving
a starting dose of 6 g/day that patient can be taking 2 tablets
with breakfast, 2 with lunch, and 2 with dinner and can be switched
to 1 with breakfast, 1 with a morning snack, 1 with lunch, 1 with a
afternoon snack and 2 with dinner if diet dictates.
[0148] The second phase of the study in the statistical plan, the
drug efficacy study, assesses the tolerability and safety of the
study drug. Drug safety is assessed by recording and monitoring
adverse events, reviewing concomitant medication use, conducting
brief physical examinations (weight, blood pressure and heart
rate), and obtaining sequential blood chemistries (including serum
phosphorus, serum calcium and selected iron parameters) and rates
of adverse events and changes in laboratory parameters.
[0149] While several particular forms of the disclosure have been
illustrated and described, it will be apparent that various
modifications and combinations of the disclosure detailed in the
text and drawings can be made without departing from the spirit and
scope of the disclosure. For example, references to materials of
construction, methods of construction, specific dimensions, shapes,
utilities or applications are also not intended to be limiting in
any manner and other materials and dimensions could be substituted
and remain within the spirit and scope of the disclosure.
* * * * *