U.S. patent application number 16/239922 was filed with the patent office on 2019-05-02 for pharmaceutical compositions comprising ferric citrate and methods for the production thereof.
This patent application is currently assigned to DEXCEL PHARMA TECHNOLOGIES LTD.. The applicant listed for this patent is DEXCEL PHARMA TECHNOLOGIES LTD.. Invention is credited to Tomer GOLD, Ron SCHLINGER, Yochai Yakovson.
Application Number | 20190125792 16/239922 |
Document ID | / |
Family ID | 54937480 |
Filed Date | 2019-05-02 |
United States Patent
Application |
20190125792 |
Kind Code |
A1 |
GOLD; Tomer ; et
al. |
May 2, 2019 |
PHARMACEUTICAL COMPOSITIONS COMPRISING FERRIC CITRATE AND METHODS
FOR THE PRODUCTION THEREOF
Abstract
The present invention relates to a pharmaceutical composition
comprising granules which include an inert core coated with ferric
citrate. The present invention also provides methods of manufacture
thereof and methods of use thereof.
Inventors: |
GOLD; Tomer; (Herzliya,
IL) ; SCHLINGER; Ron; (Tel Aviv, IL) ;
Yakovson; Yochai; (Achiya Shilo, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DEXCEL PHARMA TECHNOLOGIES LTD. |
Or Akiva |
|
IL |
|
|
Assignee: |
DEXCEL PHARMA TECHNOLOGIES
LTD.
Or Akiva
IL
|
Family ID: |
54937480 |
Appl. No.: |
16/239922 |
Filed: |
January 4, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15315942 |
Dec 2, 2016 |
10172882 |
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PCT/IL2015/050619 |
Jun 18, 2015 |
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16239922 |
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62015437 |
Jun 22, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61K 9/2027 20130101; A61K 9/2013 20130101; A61K 9/1652 20130101;
A61K 9/1682 20130101; A61K 9/2866 20130101; A61K 9/2054 20130101;
A61K 33/26 20130101; A61K 31/295 20130101; A61K 9/2077 20130101;
A61K 9/2009 20130101; A61K 9/2095 20130101; A61K 9/1676 20130101;
A61P 13/12 20180101; A61K 9/1635 20130101 |
International
Class: |
A61K 33/26 20060101
A61K033/26; A61K 9/20 20060101 A61K009/20; A61K 9/16 20060101
A61K009/16; A61K 9/28 20060101 A61K009/28; A61K 31/295 20060101
A61K031/295; A61K 9/00 20060101 A61K009/00 |
Claims
1-45. (canceled)
46. A solid pharmaceutical composition comprising: a. granules
comprising an inert core and a layer over said core, said layer
comprising ferric citrate in an amount of at least about 50 wt %
based on the weight of said composition, and optionally a binder;
and b. optionally, at least one pharmaceutically acceptable
excipient; wherein the composition is characterized by an in vitro
dissolution rate in which at least 85% of the ferric citrate drug
is released within about 15 minutes.
47. The composition of claim 46, wherein the granules are
milled.
48. The composition of claim 46, wherein the inert core comprises
microcrystalline cellulose.
49. The composition of claim 46, which comprises a binder in the
ferric citrate layer.
50. The composition of claim 49, wherein the binder is selected
from the group consisting of povidone (PVP), hydroxypropyl
cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), sodium
alginate, alginic acid, guar gum, acacia gum, xanthan gum,
carbopol, carboxymethyl cellulose, ethyl cellulose, maltodextrin,
vinylpyrrolidone/vinyl acetate copolymer, microcrystalline
cellulose, starch, and methyl cellulose, or any combination
thereof.
51. The composition of claim 46, which comprises a pharmaceutically
acceptable excipient which is an intra-granular excipient, an
extra-granular excipient, or a combination thereof.
52. The composition of claim 51, wherein the pharmaceutically
acceptable excipient is selected from the group consisting of a
binder, a disintegrating agent, a filler, an anti-tacking agent, a
lubricant, a glidant, a surfactant, a plasticizer and any
combination thereof.
53. The composition of claim 52, wherein the filler is selected
from the group consisting of a sugar, microcrystalline cellulose,
dicalcium phosphate, a sugar alcohol, a hydrogenated starch
hydrolysate, a starch, sodium carboxymethycellulose, ethyl
cellulose, and cellulose acetate, or any combination thereof.
54. The composition of claim 52, wherein the disintegrating agent
is selected from the group consisting of low-substituted
carboxymethyl cellulose sodium, cross-linked polyvinyl pyrrolidone
(crospovidone), sodium starch glycolate, cross-linked sodium
carboxymethyl cellulose, pregelatinized starch, microcrystalline
starch, water insoluble starch, calcium carboxymethyl cellulose,
low substituted hydroxypropyl cellulose, and magnesium aluminum
silicate, or any combination thereof.
55. The composition of claim 52, wherein the glidant is selected
from the group consisting of corn starch, a silica derivative,
silicon dioxide, anhydrous silica, and talc, or any combination
thereof.
56. The composition of claim 52, wherein the lubricant is selected
from the group consisting of magnesium stearate, calcium stearate,
oleic acid, caprylic acid, stearic acid, magnesium isovalerate,
calcium laurate, magnesium palmitate, behenic acid, glyceryl
behenate, glyceryl stearate, sodium stearyl fumarate, potassium
stearyl fumarate, zinc stearate, sodium oleate, sodium stearate,
sodium benzoate, sodium acetate, sodium chloride, talc, solid
polyethylene glycol, and hydrogenated vegetable oil, or any
combination thereof.
57. The composition of claim 52, wherein the binder is an
extra-granular excipient.
58. The composition of claim 46, in a form suitable for oral
administration selected from the group consisting of a tablet, a
capsule, a pill, a powder, and a pellet.
59. The composition of claim 58, in the form of a tablet.
60. The composition of claim 59, further comprising at least one
coating layer.
61. The composition of claim 60, wherein the coating layer is an
immediate release coating.
62. The composition of claim 59, wherein the tablet is
characterized by having friability of less than about 1%.
63. The composition of claim 46, comprising from about 500 mg to
about 1,500 mg ferric citrate.
64. The composition of claim 46, which is characterized by an in
vitro dissolution rate in which at least 85% of the ferric citrate
drug is released within about 15 minutes after storage of the
composition at accelerated storage conditions at 40.degree. C. and
75% relative humidity for three months.
65. A method for treating a disorder or a medical condition
selected from the group consisting of renal insufficiency, renal
failure, hyperphosphatemia, metabolic acidosis, calcium phosphate
deposition, calcification of soft tissue, kidney stones, elevated
serum calcium levels and anemia, the method comprising the step of
administering to a subject in need thereof a pharmaceutical
composition according to claim 46.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a pharmaceutical
composition comprising granules which include an inert core coated
with ferric citrate. The present invention also provides methods of
manufacture thereof and methods of use thereof.
BACKGROUND OF THE INVENTION
[0002] Ferric iron containing compounds are useful in the treatment
of a number of disorders, including, but not limited to,
hyperphosphatemia and metabolic acidosis. Previous studies and
inventions have reported the use of ferric compounds in binding
with dietary phosphates, thereby affording the control over
phosphate retention in patients suffering from renal failure and
associated hyperphosphatemia (U.S. Pat. Nos. 5,753,706; 6,903,235;
CN 1315174, U.S. Pat. No. 8,093,423). Elevated amounts of phosphate
in the blood can be removed by administering ferric iron containing
compounds such as ferric citrate. U.S. Pat. No. 5,753,706 discloses
compositions consisting of ferric citrate, ferric acetate, and
combinations thereof, in a unit dosage of about 500 mg to about
1,000 mg.
[0003] WO 2011/011541 discloses ferric citrate tablets comprising
65 wt % to 92 wt % of ferric citrate and 4.5 wt % to 30 wt %
binder, wherein at least 80% of the ferric citrate in the tablet is
dissolved in a time less than or equal to 60 minutes.
[0004] WO 2012/005340 discloses ferric citrate tablets comprising
polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl
alcohol-acrylic acid-methyl methacrylate copolymer. The tablets
comprise 70 wt % ferric citrate.
[0005] WO 2003/092658 discloses a process for preparing compressed
tablets having good mechanical strength. The pharmaceutically
active ingredient(s) and excipient(s) are granulated in the
presence of a granulating liquid comprising 5-30% microcrystalline
cellulose by a kneading or a fluidization spraying process.
[0006] WO 2008/149894 discloses a process for producing tablet or
capsule comprising a granule, wherein the granule further includes
coated core particle. The core is composed of at least 50 wt%
microcrystalline cellulose, in which the active pharmaceutical
ingredient is sprayed onto the core.
[0007] U.S. Pat. No. 6,149,943 discloses a method for preparing a
pharmaceutically active particle, which includes about 40 wt % to
75 wt % microcrystalline cellulose as inert core coated with about
25 wt % to 60 wt % pharmaceutically active ingredient. The coating
of the microcrystalline cellulose is performed in the absence of a
granulation step using a spray coating technique. Further disclosed
is a method wherein the coated particles and excipients are
compressed to form tablets.
[0008] One of the challenges of formulating ferric citrate in solid
dosage forms is its relatively high dosage. Thus, in order to
prepare dosage forms having properties (e.g., size) compatible with
the end user, ferric citrate compositions typically contain high
percentages of the active ingredient relative to excipients.
Production of such dosage forms containing ferric citrate in high
content is associated with problems such as moldability during
tableting, cracking, and difficulty in maintaining suitable
hardness, while not affecting disintegration and dissolution
properties of the dosage forms.
[0009] A need in the art exists for ferric citrate compositions
that incorporate therapeutically effective doses of the active
ingredient to effectively prevent and/or treat hyperphosphatemia
and metabolic acidosis, that overcome the aforementioned
disadvantages.
SUMMARY OF THE INVENTION
[0010] The present invention relates to a pharmaceutical
composition comprising granules comprising an inert core coated
with ferric citrate and optionally a binder. The present invention
also provides methods of manufacture thereof and methods of use
thereof.
[0011] The present invention is based in part on the unexpected
discovery that solid pharmaceutical compositions containing high
quantity/load of ferric citrate as an active ingredient can be
efficiently manufactured. The high quantity/load of ferric citrate
(preferably at least about 50% by weight of the composition) is
afforded while allowing the formation of a pharmaceutical dosage
form (e.g., a tablet) of a size that is compatible with the end
user. Moreover, the solid pharmaceutical composition is
characterized by a high in vitro dissolution rate, wherein at least
85%, preferably at least about 90%, more preferably at least about
95% of the drug is released within about 60 minutes, preferably
within about 30 minutes, and more preferably within about 15
minutes. The process for manufacturing this solid pharmaceutical
composition is a one pot process that is simple, efficient and cost
effective to implement.
[0012] According to one aspect, the present invention provides a
solid pharmaceutical composition comprising: (a) granules
comprising an inert core and a layer over said core, said layer
comprising ferric citrate in an amount of at least about 50 wt %
based on the weight of said composition, and (b) optionally, at
least one pharmaceutically acceptable excipient. In one embodiment,
the pharmaceutically acceptable excipient is an intra-granular
excipient. In another embodiment, the pharmaceutically acceptable
excipient is an extra-granular excipient. In yet another
embodiment, the pharmaceutical composition comprises both an
intra-granular excipient and an extra-granular excipient. In one
embodiment, the pharmaceutically acceptable excipient comprises a
binder. In another embodiment, the granules are milled.
[0013] According to another aspect, the present invention provides
a solid pharmaceutical composition comprising: (a) milled granules
comprising an inert core and a layer over said core, said layer
comprising ferric citrate in an amount of at least about 50 wt %
based on the weight of said composition, and optionally a binder,
and (b) optionally, at least one pharmaceutically acceptable
excipient.
[0014] According to some embodiments, the amount of ferric citrate
is at least about 60% by weight of the composition. In other
embodiments, the amount of ferric citrate is at least about 70% by
weight of the composition. The high load of ferric citrate in the
composition allows for the incorporation of relatively high dose of
the active ingredient, e.g., at least about 500 mg to at least
about 1,500 mg ferric citrate per dosage form while maintaining a
size that is compatible with the end user.
[0015] According to some embodiments, the granules are prepared by
applying a composition comprising ferric citrate and optionally a
binder over the inert core. The application of a composition
comprising ferric citrate over the inert core may be performed as
is known in the art, for example using spray coating. The granules
are optionally milled. The granules may further be blended with at
least one pharmaceutically acceptable excipient, and further
processed to produce a solid pharmaceutical dosage form, e.g., a
tablet.
[0016] According to some embodiments, the inert core comprises
microcrystalline cellulose (e.g.,)AVICEL.RTM..
[0017] According to certain embodiments, the weight ratio between
the inert core and the ferric citrate coating layer is about 1 to
about 8-300 (1:8 to 1:300). In other embodiments, the weight ratio
between the inert core and the ferric citrate coating layer is
about 1 to about 8-150 (1:8 to 1:150). In additional embodiments,
the weight ratio between the inert core and the ferric citrate
coating layer is about 1 to about 100-150 (1:100 to 1:150).
[0018] According to other embodiments, the composition further
comprises at least one excipient selected from the group consisting
of a binder, a disintegrating agent, a filler, an anti-tacking
agent, a lubricant, a glidant, a surfactant, a plasticizer or any
combination thereof with each possibility representing a separate
embodiment of the present invention. These excipients are
preferably blended with the granules as intra-granular and/or
extra-granular excipients, so as to form the solid dosage forms of
the invention. It is understood that a binder may be present in the
ferric citrate layer (i.e., intra-granular excipient), or as an
extra-granular excipient, or a combination thereof. Each
possibility represents a separate embodiment of the present
invention. According to other embodiments, the ferric citrate layer
further comprises a binder. In one embodiment, the binder is
povidone (PVP). In another embodiment, the binder is starch,
pregelatinized starch or a combination thereof. Each possibility
represents a separate embodiment of the present invention.
[0019] Any pharmaceutically acceptable excipients can be used in
the compositions of the present invention. In one embodiment, the
filler/diluent is microcrystalline cellulose. In another
embodiment, the disintegrating agent is crospovidone. In another
embodiment, the glidant is colloidal silicon dioxide. In another
embodiment, the lubricant is sodium stearyl fumarate. In yet
another embodiment, the lubricant is calcium stearate. Additional
excipients suitable for use in the context of the present invention
are described herein below.
[0020] According to some embodiments, the composition of the
present invention has an in vitro dissolution profile at pH of
about 1 to about 7, preferably pH of about 4 to about 7, in which
at least about 85% of the drug is released from the composition
within about 60 minutes, preferably within about 30 minutes, and
more preferably within about 15 minutes. In certain embodiments,
the composition has an in vitro dissolution profile, when measured
in a type II Paddle dissolution apparatus in McIlvaine buffer 98%
(pH 4.0), in which at least about 85% of the drug/pharmaceutical
composition is released within about 60 minutes, preferably within
about 30 minutes, and more preferably within about 15 minutes. In
some embodiments, at least about 90% of the drug/pharmaceutical
composition is released within about 60 minutes, preferably within
about 30 minutes, and more preferably within about 15 minutes. In
other embodiments, at least about 95% of the drug/pharmaceutical
composition is released within about 60 minutes, preferably within
about 30 minutes, and more preferably within about 15 minutes.
[0021] According to some embodiments, the composition is in a form
suitable for oral administration. In accordance with these
embodiments, the composition is in a form selected from the group
consisting of a tablet, a capsule, a pill, a powder and a pellet.
Each possibility represents a separate embodiment of the present
invention. In further embodiments, the composition may be filled
into capsules or sachet for oral administration. In other
embodiments, the composition (e.g., in the form of a powder) may be
mixed with a liquid thereby forming a suspension or solution for
oral administration. In one currently preferred embodiment, the
present invention is directed to a solid dosage form in the form of
a tablet. According to some embodiments, the present invention
relates to a tablet obtainable by compressing the pharmaceutical
composition as described herein.
[0022] According to other embodiments, the composition further
comprises at least one coating layer. In one embodiment, the
coating layer is an immediate release coating. In certain
embodiments, the composition further comprises at least one coating
layer over the ferric citrate layer.
[0023] According to some embodiments, the composition comprises
residual amount of water in an amount of about 1-20% by weight of
the composition, e.g., about 5-20% by weight of the composition. In
certain embodiments, the granules comprise residual amount of water
in an amount of about 1-20% by weight of the composition, e.g.,
about 5-20% by weight of the composition prior to being compressed
into a tablet.
[0024] According to some embodiments, the composition of the
present invention has a BET (Brunauer Emmett Teller) active surface
area of less than about 10 sq. m/g, preferably less than about 5
sq. m/g, and more preferably less than about 3 sq. m/g.
[0025] According to yet another aspect, the present invention
provides a method for preparing granules comprising ferric citrate,
the method comprising the steps of: (a) dissolving ferric citrate
and optionally a binder in an aqueous medium to obtain a solution;
(b) applying the solution obtained in step (a) onto an inert core
so as to obtain granules; and (c) optionally milling the granules.
In one embodiment, step (a) further includes the use of a binder.
In another embodiment, the method further includes the step of
drying the granules obtained in step (b) or the milled granules
obtained in step (c). In yet another embodiment, the optional
milling step is performed.
[0026] According to some embodiments, the method further comprises
the step of blending the granules with at least one
pharmaceutically acceptable excipient. The at least one
pharmaceutically acceptable excipient may be an intra-granular
and/or an extra-granular excipient.
[0027] According to other embodiments, the step of dissolving the
ferric citrate further includes addition of one or more of a
buffering agent, wetting agent or surfactant.
[0028] According to certain embodiments, the aqueous medium is
water. In further embodiments, the water is hot water. According to
some embodiments, the hot water is at a temperature of between
about 40.degree. C. to about 80.degree. C. According to other
embodiments, the solution is kept heated at above about 80.degree.
C. throughout the process.
[0029] According to certain embodiments, the step of applying the
solution obtained in step (a) onto an inert core comprises the use
of spray coating.
[0030] According to some embodiments, the granules are milled to
form a powder having a mean particle size of less than about 400
microns. In various embodiments, the granules are milled to form a
powder wherein about 50% of the particles have a particle size of
less than about 75 microns.
[0031] According to another aspect, the present invention further
provides a method for preparing a composition comprising granules
comprising ferric citrate, the method comprising the step of
applying at least one coating layer onto said composition.
[0032] According to some embodiments, the present invention
provides a method for preparing a tablet comprising ferric citrate,
the method comprising the steps of: (a) dissolving ferric citrate
and optionally a binder in an aqueous medium to obtain a solution;
(b) applying the solution obtained in step (a) onto an inert core
so as to obtain granules; (c) optionally milling the granules; (d)
optionally drying the granules obtained in step (b) or the milled
granules obtained in step (c); (e) blending the granules obtained
in step (b) or the milled granules obtained in step (c) or the
dried granules obtained in step (d) with at least one
pharmaceutically acceptable excipient; and (f) compressing the
blend of step (e) to obtain a tablet comprising ferric citrate. In
one embodiment, step (a) further includes the use of a binder. In
another embodiment, the optional drying step is performed. In yet
another embodiment, the optional milling step is performed.
[0033] According to yet another aspect, the present invention
provides a method for treating a disorder or a medical condition in
a subject, selected from the group consisting of renal
insufficiency, renal failure, hyperphosphatemia, metabolic
acidosis, calcium phosphate deposition, calcification of soft
tissue, kidney stones, elevated serum calcium levels and anemia,
the method comprising the step of administering to a subject in
need thereof a pharmaceutical composition comprising ferric citrate
as described herein.
[0034] According to some embodiments, the subject is a mammal
According to other embodiments, the subject is a human. According
to further embodiments, the administration route is oral.
[0035] Further embodiments and the full scope of applicability of
the present invention will become apparent from the detailed
description given hereinafter. However, it should be understood
that the detailed description and specific examples, while
indicating preferred embodiments of the invention, are given by way
of illustration only, since various changes and modifications
within the spirit and scope of the invention will become apparent
to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
Ferric Citrate Compositions
[0036] According to some aspects and embodiments, the present
invention provides a solid pharmaceutical composition comprising:
(a) granules comprising an inert core and a layer over said core,
said layer comprising ferric citrate in an amount of at least about
50 wt % based on the weight of said composition and optionally a
binder; and (b) optionally, at least one pharmaceutically
acceptable excipient.
[0037] According to other aspects and embodiments, the present
invention provides a solid pharmaceutical composition comprising:
(a) milled granules comprising an inert core and a layer over said
core, said layer comprising ferric citrate in an amount of at least
about 50 wt % based on the weight of said composition, and
optionally a binder; and (b) optionally, at least one
pharmaceutically acceptable excipient.
[0038] According to certain aspects and embodiments, provided
herein is a solid pharmaceutical composition comprising granules
comprising an inert core and a layer comprising ferric citrate
which is applied to the inert core such that the amount of ferric
citrate is at least about 50 wt % based on the weight of said
composition. The composition of the present invention may
optionally comprise at least one pharmaceutically acceptable
excipient which may be an intra-granular excipient, an
extra-granular excipient or a combination thereof. Each possibility
represents a separate embodiment of the present invention. In
various embodiments, the granules are milled.
[0039] The solid pharmaceutical compositions of the present
invention exert surprisingly advantageous properties including
improved dissolution and stability. The present invention
demonstrates for the first time that by applying a ferric citrate
solution over an inert core to obtain granules, a dosage form
(e.g., tablet) having increased solubility and stability can be
obtained, in comparison to a dosage form prepared from conventional
granules which are not prepared by applying a ferric citrate
solution over an inert core.
[0040] The granules, according to the principles of the present
invention, are prepared by applying (e.g. using spray coating) a
composition comprising ferric citrate and optionally a binder over
the inert core so as to obtain granules. The granules are
optionally milled. The granules are then optionally blended with at
least one pharmaceutically acceptable excipient.
[0041] The granules thus obtained may further be processed as is
known in the art to a solid dosage form particularly suitable for
oral administration. The solid dosage form may be in a form
selected from the group consisting of a tablet, a capsule
(including a hard shell capsule or a soft shell capsule), a pill, a
powder, and a pellet. Each possibility represents a separate
embodiment of the present invention. In an exemplary embodiment,
the present invention provides a powder suitable for oral
administration, said powder can be filled into capsules or sachet
to be administered as sprinkle dosage form or mixed with a liquid
prior to administration thereby forming a suspension or solution.
In other embodiments, the present invention provides a tablet
suitable for oral administration. In certain embodiments, the
tablet disclosed herein comprises granules comprising an inert core
and a layer over said core, said layer comprising ferric citrate in
an amount of at least about 50 wt % based on the weight of said
composition, and further comprises at least one binder and at least
one pharmaceutically acceptable excipient. In other embodiments,
the present invention provides a tablet comprising milled granules
comprising an inert core and a layer over said core, said layer
comprising ferric citrate in an amount of at least about 50 wt %
based on the weight of said composition, and further comprising at
least one binder and at least one pharmaceutically acceptable
excipient. In some embodiments, the tablet is able to sustain
compression at a level of about 40 to about 300 N, for example
about 100 to about 300 N, preferably about 150 to about 300 N. In
certain embodiments, the tablet is further characterized by having
friability of less than about 1%, for example about 0.2% to about
1%. In additional embodiments, the disintegration of said tablet as
measured in e.g. USP general method <701>is less than about
60 minutes, for example about 50, 40, 30, 20 or 10 minutes. In one
embodiment, the disintegration of the tablet is performed in less
than about 50 seconds.
[0042] The active ingredient, ferric citrate, can be prepared in
accordance with any method known in the art or obtained from any
source, including any commercial source. It is contemplated that
any pharmaceutically acceptable form of ferric citrate including,
but not limited to, solvates (e.g. hydrates), polymorphs, and
pseudopolymorphs thereof are within the scope of the present
invention. According to some embodiments, the amount of ferric
citrate is at least about 60% by weight of the composition. In
other embodiments, the amount of ferric citrate is at least about
70% by weight of the composition.
[0043] According to certain aspects and embodiments, the weight
ratio between the inert core and the coating layer is about 1 to
about 8-300 (1:8 to 1:300). According to some embodiments, the
weight ratio between the inert core and the coating layer is about
1 to about 8-150 (1:8 to 1:150), preferably is about 1 to about
100-150 (1:100 to 1:150), or about 1 to about 9-120 (1:9 to 1:120).
The compositions of the present invention allow for high load of
active ingredient vs. inactive excipients, thus enabling
incorporation of a high dosage of ferric citrate e.g., at least
about 500 mg to at least about 1,500 mg per dosage form, for
example at least about 500, 600, 700, 800, 900, 1,000, 1,100,
1,200, 1,300, 1,400 or 1,500 mg while keeping the dosage form at a
size that is compatible with the end user.
[0044] According to some embodiments, the inert core comprises
microcrystalline cellulose in an amount of about 0.1 wt % to about
50 wt % based on the weight of said composition. According to other
embodiments, the inert core comprises microcrystalline cellulose in
an amount of about 1 wt % to about 50 wt % based on the weight of
said composition. According to yet other embodiments, the inert
core comprises microcrystalline cellulose in an amount of about 5
wt % to about 20 wt % based on the weight of said composition.
According to additional embodiments, the inert core comprises
microcrystalline cellulose in an amount of about 5 wt % based on
the weight of said composition.
[0045] The inert core of the compositions described herein can be
comprised of any pharmaceutically inert compound, e.g., a filler.
The inert core onto which the ferric citrate and optional binder is
applied is usually comprised of sugars and starch (e.g. nonpareil
seeds) or cellulosic materials, ionic compositions (e.g. calcium
dibasic phosphate) or combinations thereof, for example sugar
derivatives such as lactose, sucrose, hydrolyzed starch
(maltodextrins) or celluloses or mixtures thereof. A currently
preferred excipient for the inert core is microcrystalline
cellulose)(AVICEL.RTM.. Any pharmaceutically acceptable AVICEL.RTM.
grade can be used in the context of the invention, e.g.,
AVICEL.RTM. 101, AVICEL.RTM. 102 and the like.
[0046] According to some embodiments, the binder in the ferric
citrate layer is selected from the group consisting of povidone
(PVP), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose
(HPMC), sodium alginate, alginic acid, guar gum, acacia gum,
xanthan gum, carbopol, cellulose gum (carboxymethyl cellulose),
ethyl cellulose, maltodextrin, PVP/VA (vinylpyrrolidone/vinyl
acetate copolymer), microcrystalline cellulose, starch (partially
or fully pregelatinized starch such as starch 1500) and methyl
cellulose, or any combination thereof among others. Each
possibility represents a separate embodiment of the invention. A
currently preferred binder is povidone (PVP).
[0047] In addition to the binder in the ferric citrate layer, the
compositions of the invention may further include a binder as an
extra-granular excipient. Any one of the binders described above is
suitable for use as an extra-granular excipient. In some
embodiments, a binder is present as an intra-granular excipient, an
extra-granular excipient or a combination thereof. Each possibility
represents a separate embodiment of the present invention.
[0048] According to other embodiments, the composition further
comprises at least one excipient selected from the group consisting
of a binder, disintegrating agent, a filler, an anti-tacking agent,
a lubricant, a glidant, a surfactant, a plasticizer or any
combination thereof. The excipient may by intra-granular, i.e., it
is incorporated in the granules of the invention. In alternative
embodiments, the excipient may be extra-granular, i.e., it may be
blended with the granules of the invention as an extra-granular
excipient.
[0049] Any pharmaceutically acceptable filler/diluent can be used
in the compositions of the present invention. Non-limiting examples
of suitable fillers include sugars (such as lactose, glucose,
fructose, or sucrose), microcrystalline cellulose, dicalcium
phosphate, a sugar alcohol (such as sorbitol, mannitol, maltitol,
lactitol, xylitol, isomalt, and erythritol), a hydrogenated starch
hydrolysate, a starch (such as corn starch, or potato starch), or
sodium carboxymethycellulose, ethylcellulose, cellulose acetate and
any combination thereof. Each possibility represents a separate
embodiment of the present invention. In one currently preferred
embodiment, the filler/diluent is microcrystalline cellulose.
[0050] Any pharmaceutically acceptable disintegrant can be used in
the compositions of the present invention. Non-limiting examples of
suitable disintegrants include low-substituted carboxymethyl
cellulose sodium, cross-linked polyvinyl pyrrolidone
(crospovidone), sodium starch glycolate, cross-linked sodium
carboxymethyl cellulose, pregelatinized starch (starch 1500),
microcrystalline starch, water insoluble starch, calcium
carboxymethyl cellulose, low substituted hydroxypropyl cellulose,
magnesium aluminum silicate, and any combination thereof. Each
possibility represents a separate embodiment of the present
invention. In one currently preferred embodiment, the
disintegrating agent is crospovidone (cross-linked povidone).
[0051] Any pharmaceutically acceptable glidant can be used in the
compositions of the present invention. Non-limiting examples of
suitable glidants include corn starch, silica derivatives,
including silicon dioxide, silica anhydrous, talc and any
combination thereof. Each possibility represents a separate
embodiment of the present invention. In one currently preferred
embodiment, the glidant is colloidal silicon dioxide.
[0052] Any pharmaceutically acceptable lubricant can be used in the
compositions of the present invention. Non-limiting examples of
suitable lubricants include magnesium stearate, calcium stearate,
oleic acid, caprylic acid, stearic acid, magnesium isovalerate,
calcium laurate, magnesium palmitate, behenic acid, glyceryl
behenate, glyceryl stearate, sodium stearyl fumarate, potassium
stearyl fumarate, zinc stearate, sodium oleate, sodium stearate,
sodium benzoate, sodium acetate, sodium chloride, talc, solid
polyethylene glycols, hydrogenated vegetable oil, and any
combination thereof. Each possibility represents a separate
embodiment of the present invention. In one currently preferred
embodiment, the lubricant is sodium stearyl fumarate. In another
currently preferred embodiment, the lubricant is calcium
stearate.
[0053] Non-limiting examples of anti-tacking agents that may
optionally be employed include magnesium stearate, calcium
stearate, stearic acid, talc, colloidal silicon and the like among
others. Each possibility represents a separate embodiment of the
invention.
[0054] Non-limiting examples of plasticizers that may optionally be
employed include dibutyl sebacate, polyethylene glycol,
polypropylene glycol, dibutyl phthalate, diethyl phthalate,
triethyl citrate, tributyl citrate, acetylated monoglyceride,
acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl
benzoate, butyl and/or glycol esters of fatty acids, refined
mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol
and sorbitol among others. Each possibility represents a separate
embodiment of the invention.
[0055] The surfactants that may optionally be employed in the
present invention may be non-ionic, anionic or cationic. Typically,
surfactants may have one lipophilic and one hydrophilic group in
the molecule. The surfactant may optionally comprise one or more of
soaps, detergents, emulsifiers, dispersing and wetting agents. More
specifically, surfactants may optionally comprise, for example, one
or more of stearyl triethanolamine, sodium lauryl sulfate, sodium
taurocholate, laurylaminopropionic acid, lecithin, benzalkonium
chloride, benzethonium chloride and glycerin monostearate; and
hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, carboxymethylcellulose sodium,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and
hydroxypropylcellulose among others. Each possibility represents a
separate embodiment of the invention.
[0056] According to other embodiments, the composition may
optionally further comprises additional excipients, provided that
such additional excipients do not interfere or adversely affect the
desired biological activity of the composition of the present
invention. For example: sweetener (such as acesulfame potassium and
sucralose), flavorant (such as citric acid powder, strawberry
flavor, menthol, orange or mint flavor, or a combination thereof),
breath-freshener and/or colorant (pigment or dye). Flavorants and
sweeteners are particularly useful when the active ingredient has a
bitter taste, the masking of which would increase patient
compliance as ferric citrate may have an unpleasant "iron"
taste.
[0057] According to additional embodiments, the composition further
comprises at least one coating layer over the ferric citrate layer
or alternatively over the entire solid dosage form, for example, a
film coating. The coating layer is preferably an immediate release
coating, but may also be an extended, controlled or delayed release
coating. In one embodiment, when a functional coating such as
extended, controlled or delayed release is applied to the granules,
the step of milling the granules is avoided. The coating over the
ferric citrate layer or over the entire solid dosage form, may
comprise polymers which are preferably water soluble (including
cellulosic polymers such as hydroxypropyl methylcellulose (HPMC) or
hydroxypropyl cellulose (HPC)), polyvinyl alcohol (PVA),
polyvinylpyrrolidone (PVP), or polyethylene glycol, among others.
Sugar/lactose coating is also optional. Each possibility represents
a separate embodiment of the invention. In one currently preferred
embodiment, the coating layer comprises hydroxypropyl
methylcellulose (HPMC) which does not contain iron compounds.
[0058] According to some embodiments, the coating layer may further
include a taste-masking coating. The taste-masking coating may
comprise, but is not limited to, one or more of the following
polymers: water insoluble polymers (water insoluble cellulosic
polymers such as ethylcellulose), acrylate polymers ((meth)acrylate
based polymers such as Eudragit.RTM. RS, Eudragit.RTM. RL and
Eudragit.RTM. EPO) and water soluble polymers (water soluble
cellulosic polymers such as hydroxypropylcellulose (HPC) and
hydroxypropyl methylcellulose (HPMC)) or mixtures thereof among
others. Each possibility represents a separate embodiment of the
invention.
[0059] According to various embodiments, the composition comprises
residual amount of water in an amount of about 1-20% by weight of
the composition, preferably about 5-20% by weight of the
composition. In certain embodiments, the granules comprise residual
amount of water in an amount of about 1-20% by weight of the
composition, e.g., about 5-20% by weight of the composition.
[0060] According to certain embodiments, the compositions of the
present invention have an immediate release profile. The
compositions have an in vitro dissolution profile wherein at least
about 85% of the drug is released from the composition within about
60 minutes, preferably within about 30 minutes, and more preferably
within about 15 minutes. In one embodiment, at least about 90% of
the drug is released within about 60 minutes, preferably within
about 30 minutes, and more preferably within about 15 minutes. In
another embodiment, at least about 95% of the drug is released
within about 60 minutes, preferably within about 30 minutes, and
more preferably within about 15 minutes.
[0061] The dissolution tests of the compositions may be performed
in any suitable apparatus, such as a type II Paddle Dissolution
Apparatus (e.g. Distek Evolution 6100), using a rotation speed of
100 rpm and temperature of 37.degree. C..+-.0.5.degree. C. The
dissolution media may be, for example McIlvaine buffer 98% (pH
4.0). The release can be determined using a UV-VIS instrument such
as Agilent 8453 UV-VIS, 360 nm with 600 nm background.
Alternatively, the dissolution tests of the compositions may be
performed in USP Apparatus II (Paddle) (VanKel or Distek or
equivalent) using a rotation speed of 100 rpm and temperature of
37.degree. C..+-.0.5.degree. C. The dissolution media may be, for
example Mcllavaine buffer pH 4 or 0.1N HCl or acetate buffer pH 4.5
or phosphate buffer pH 6.8 or EDTA solution; with samples
filtration: 20 mic cannula style filter. Measurements may be
performed using e.g. UV-VIS spectrophotometer or by HPLC system
using Reverse Phase C18 column.
[0062] According to some embodiments, the coated granules (inert
core coated with ferric citrate) may have a BET (Brunauer Emmett
Teller) active surface area of less than about 10 sq. m/g,
preferably less than about 5 sq. m/g, and more preferably less than
about 3 sq. m/g. BET analysis can be performed according to the
standards set forth in the United States Pharmacopeia (USP) (United
States Pharmacopeia 37-National Formulary 32, p. 476-479) (United
States Pharmacopeial Convention, Rockville, Md., 2014).
[0063] According to various embodiments, the present invention
provides a stable composition comprising ferric citrate. In some
embodiments, the composition of the present invention is stable
even after accelerated storage conditions (e.g. 40.degree. C. and
75% relative humidity). In one embodiment, the composition provides
an in vitro dissolution profile wherein at least about 85%,
preferably at least about 90% of the drug is released from the
composition within about 60 minutes, preferably within about 30
minutes, and more preferably within about 15 minutes after three
months at 40.degree. C. and 75% relative humidity, using any of the
dissolution tests described herein.
Process for Manufacturing Ferric Citrate Compositions
[0064] According to some embodiments, the present invention
provides a method for preparing granules comprising ferric citrate,
the method comprising the steps of: (a) dissolving ferric citrate
and optionally a binder in an aqueous medium, (e.g., water,
preferably hot water) to obtain a solution; (b) applying the
solution obtained in step (a) onto an inert core so as to obtain
granules; and (c) optionally milling the granules. According to
other embodiments, the present invention provides a method for
preparing a tablet, the method further comprising the steps of: (d)
optionally drying the granules obtained in step (b) or the milled
granules obtained in step (c); (e) blending the granules obtained
in step (b) or the milled granules obtained in step (c) or the
dried granules obtained in step (d) with at least one
pharmaceutically acceptable excipient; and (f) compressing the
blend of step (e) to obtain a tablet comprising ferric citrate. The
at least one pharmaceutically acceptable excipient which is blended
with the granules or the milled granules or the dried granules may
be an intra-granular excipient, an extra-granular excipient, or a
combination thereof.
[0065] In one embodiment, the method of the present invention
comprises step (d) of drying the granules obtained in step (b) or
the milled granules obtained in step (c) such that the granules
comprise residual amount of water in an amount of about 1-20% by
weight of the composition, e.g., about 5-20% by weight of the
composition. In accordance with these embodiments, the residual
amount of water of about 1-20%, for example about 5-20% is present
in the granules prior to them being further processed such as for
example, compressed into a tablet. In particular embodiments, the
method of the present invention does not include a step of
post-tableting drying.
[0066] According to other embodiments, the step of dissolving the
ferric citrate further includes addition of one or more of a
buffering agent for controlling and/or adjusting the pH value of
the solution. Further, wetting agents or surfactants may be added.
Examples of suitable surfactants include, but are not limited to,
non-ionic, anionic or cationic surfactants as described above.
[0067] According to some embodiments, the ferric citrate and
optional binder are dissolved in hot water which is at a
temperature of between about 30.degree. C. to about 80.degree. C.,
more preferably between about 40.degree. C. to about 80.degree. C.
In one currently preferred embodiment, the solution is kept heated
to above about 80.degree. C., for example about 80.degree. C. to
about 90.degree. C., throughout the process.
[0068] The hot solution may then be applied, for example by spray
coating, onto the inert core. Non-limiting examples for spray
coating apparatus which may be employed in the present invention
include rotary disks, single-fluid high pressure swirl nozzles,
two-fluid nozzles or ultrasonic nozzles, Single stage dryer, Two
stage dryer, Horizontal dryer, Fluidized spray coater (e.g.,
TURBOJET), Multi stage drier, Compact spray dryer, Integrated
filter drier, FILTERMAT.RTM. dryer, including, e.g., Glatt,
Gea-Niro, BWI Huttlin, Allgaier among others. Each possibility
represents a separate embodiment of the invention.
[0069] According to some embodiments, the final granules are milled
to form a powder having a mean particle size of about 400 microns
or less, for example about 400, 300, 200, or 100 microns. In
certain embodiments, at least about 50% of the granules have a
particle size of less than about 75 microns, for example about
25-75 microns, preferably about 45-75 microns. The equipment used
to mill the granules include for example, fluid energy milling,
impact milling, cutting milling, compression milling, screening
milling, tumbling milling, and oscillating milling. Each
possibility represents a separate embodiment of the present
invention. Sieving of the milled granules may also be performed
using vibrators or shakers as is known in the art.
[0070] According to some embodiments, the method further comprises
the step of blending/mixing said granules with at least one
pharmaceutically acceptable excipient, which may be an
intra-granular excipient, an extra-granular excipient, or a
combination thereof. The mixing process can be achieved using any
suitable type of mixer or blender. Non-limiting examples include:
simple paddle mixer, ribbon and/or tumbling mixers, plow blenders
and drum agglomerators, V-blenders, double cone blenders, slant
cone blenders, twin shell blenders, e.g., PATTERSON KELLEY V
Blenders, GEMCO double cone blenders, diffusion blender and the
like among others. Each possibility represents a separate
embodiment of the present invention.
[0071] According to some embodiments, the granules mixed with at
least one pharmaceutically acceptable excipient or the milled
granules mixed with at least one pharmaceutically acceptable
excipient may optionally be compressed into a tablet. The tableting
process can be achieved using any suitable tableting equipment.
Non-limiting examples include: mini press, single or double punch
or rotary tablet press such as Killian, Korsch, Colton, Manesty,
Stokes, Vector and the like among others.
[0072] According to some embodiments, the method for preparing the
dosage forms of the invention further comprises the step of
applying at least one coating layer onto said dosage form.
Therapeutic Uses
[0073] According to certain embodiments, the present invention
provides a method for treating a disorder and/or medical condition
in a subject, selected from the group consisting of renal
insufficiency, renal failure, hyperphosphatemia and/or metabolic
acidosis, calcium phosphate deposition, calcification of soft
tissue, kidney stones, elevated serum calcium levels and anemia.
The method comprises the step of administering to a subject in need
thereof a ferric citrate pharmaceutical composition as described
herein.
[0074] As used herein, the term "administering" refers to bringing
in contact with the composition of the present invention.
Administration can be accomplished to cells or tissue cultures, or
to living organisms, for example mammals, preferably humans.
According to other embodiments, the administration route is
oral.
[0075] The terms "treating" or "treatment" are interchangeable and
refer to any one or more of reduction in the progress of the
condition (including the rate of progress), a halt in the rate of
progress, amelioration of the condition and cure of the condition.
Treatment as a prophylactic measure (i.e. prophylaxis) is also
included. "Treating" and "treatment" also refer to reducing the
symptoms associated with the condition that is being treated.
[0076] The terms "renal insufficiency" and/or "renal failure" refer
to subjects having acute, chronic and/or end-stage renal failure.
The subject may optionally be on dialysis treatment which may be
hemodialysis or peritoneal dialysis.
[0077] According to another aspect, the present invention provides
use of a composition as described herein, for the manufacture of a
medicament for treating a disorder and/or medical condition
selected from the group consisting of renal insufficiency, renal
failure, hyperphosphatemia and/or metabolic acidosis, calcium
phosphate deposition, calcification of soft tissue, kidney stones,
and elevated serum calcium levels.
[0078] According to yet another aspect, the present invention
provides a composition as described herein, for use in treating a
disorder and/or medical condition selected from the group
consisting of renal insufficiency, renal failure, hyperphosphatemia
and/or metabolic acidosis, calcium phosphate deposition,
calcification of soft tissue, kidney stones, and elevated serum
calcium levels.
[0079] The pharmaceutical compositions of the present invention may
be administered at a dose of about 10 to about 500 mg/kg/day of
ferric citrate, for example about 50 to about 400 mg/kg/day,
preferably about 100 to about 300 mg/kg/day. It is contemplated
that the dose at which the pharmaceutical composition is
administered comprises an amount effective to achieve its intended
purpose. The actual amount effective for a particular application
will depend, inter alia, on the condition being treated. The dosage
and frequency (single or multiple doses) of the pharmaceutical
composition can vary depending upon a variety of factors, including
route of administration; size, age, sex, health, body weight, body
mass index, and diet of the recipient; nature and extent of
symptoms of the disease being treated; presence of other diseases
or other health-related problems; kind of concurrent treatment; and
complications from any disease or treatment regimen. Additional
factors include, but are not limited to, potency, relative
bioavailability, presence and severity of adverse side effects,
preferred mode of administration, and the toxicity profile. Doses
and frequency may be initially determined in vitro, for example
from cell culture assays or in vivo using various animal
models.
[0080] As used herein and in the appended claims the singular forms
"a", "an" and "the" include plural references unless the context
clearly dictates otherwise. Thus, for example, reference to "a
layer" includes a single layer or plurality of such layers and
equivalents thereof known to those skilled in the art, and so
forth.
[0081] The principles of the present invention are demonstrated by
means of the following non-limiting examples.
EXAMPLES
Example 1: Process for Preparing Ferric Citrate Tablets without
Applying the Ferric Citrate Solution onto Inert Cores
[0082] (a) Milling
[0083] Ferric citrate was milled using Clit mill (hammers) with 500
micron sieve in (i) 1,000 rpm or (ii) 4,500 rpm to form a fine
powder.
[0084] The particle size measured for (i) was less than about 300
microns (about 40% of the particles had a particle size of less
than about 75 microns). The particle size measured for (ii) was
less than about 250 microns (about 60% of the particles had a
particle size of less than about 75 microns).
[0085] (b) Blending Milled Ferric Citrate
[0086] The following substances were homogenously blended (Table
1):
TABLE-US-00001 TABLE 1 Substance gr Milled Ferric Citrate (i) or
(ii) 450.0 Povidone K-30 18.0 Crospovidone XL 10 29.2 AVICEL .RTM.
102/microcrystalline 72.3 cellulose Silicon dioxide/colloidal
silicon 2.9 dioxide Sodium stearyl fumarate 11.7
[0087] (c) Tableting:
[0088] The blend from (b) was compressed into 1,560 mg tablets,
with the following composition (Table 2):
TABLE-US-00002 TABLE 2 Substance mg/tab % Milled Ferric citrate (i)
or (ii) 1201.9 77.0 Microcrystalline cellulose PH102 193.0 12.4
Povidone K 30 48.1 3.1 Crospovidone 78.0 5.0 Colloidal silicon
dioxide 7.8 0.5 Sodium stearyl fumarate 31.2 2.0 Total 1560.0
100.0
[0089] In most instances, it was impossible to obtain tablets from
the blend of milled ferric citrate (i) due to capping (i.e.,
partial or complete separation of the top or bottom of the
tablet).
Example 2: In Vitro Dissolution Test
[0090] Dissolution testing was conducted to the pharmaceutical
composition prepared according to Example 1. Testing was performed
on entire uncapped tablets. The following conditions were used:
[0091] Dissolution instrument: Distek Evolution 6100 [0092] Medium:
pH 4.0 McIlvaine buffer [0093] Apparatus USP: Apparatus II (paddle
method); 100 rpm [0094] Temperature: 37.degree. C..+-.0.5.degree.
C. [0095] Time: Samples taken at 15 and 45 minutes [0096] UV-VIS
Instrument: Agilent 8453 UV-VIS; 360 nm with 600 nm background
[0097] The Dissolution results for tablets pressed with (ii) were
46% dissolved in 15 min and 72% dissolved in 45 min.
Example 3: Tableting of Unmilled Ferric Citrate
[0098] Unmilled Ferric citrate was homogenously blended with the
same excipients as described in table (1), and pressed into tablets
with the same composition as described in table (2).
[0099] It was impossible to obtain tablets from the blend of
unmilled ferric citrate due to capping.
Example 4: Process for Preparing Ferric Citrate Tablets According
to Embodiments of the Present Invention
[0100] (a) Preparing the granules:
[0101] 1.60 kg of ferric citrate and 0.64 kg PVP K-30/povidone were
dissolved in 3.2 Liter hot purified water (80.degree. C.) to attain
a visually clear solution. The solution was then applied onto
pre-heated 1.50 kg of AVICEL.RTM. 101/microcrystalline cellulose
using spray coating in fluid bed coater TURBOJET. Additional clear
solutions containing 1.60 kg of ferric citrate and 0.64 kg PVP
K-30/povidone dissolved in 3.2 Liter hot purified water (80.degree.
C.) were repeatedly applied onto the thus formed granules until
gaining a ferric citrate content of at least 80%. To avoid
solidification of the product, the solution was kept heated above
80.degree. C. and stirred throughout the process.
Process parameters: Inlet air temp: 40-60.degree. C. Product temp:
30-40.degree. C. Outlet air temp: 35-45.degree. C. Solution spray
rate: 3-30 g/min Nozzle diameter: 0.8 mm Atomizing pressure: 1-2
bar
[0102] (b) Milling:
[0103] The final granules were milled using Clit mill (hammers)
with 500 micron sieve to form a powder. The mean particle size
measured was less than about 400 microns. Furthermore, about 50% of
the particles had a particle size of less than about 75
microns.
[0104] (c) Blending the milled granules with pharmaceutically
acceptable excipients:
[0105] The following substances were homogenously blended (Table
3):
TABLE-US-00003 TABLE 3 Substance gr Milled Ferric citrate granules
1781.7 Crospovidone XL 10 108.8 AVICEL .RTM. 102/microcrystalline
231.1 cellulose Silicon dioxide/colloidal silicon 10.9 dioxide
Sodium stearyl fumarate 43.5
[0106] (d) Tableting:
[0107] The blend from (c) was compressed into 1,360 mg tablets,
with the following composition (Table 4):
TABLE-US-00004 TABLE 4 Substance mg/tab % Granulate: Ferric citrate
1000.0 73.5 Microcrystalline cellulose 73.6 5.4 PH101 Povidone K 30
40.0 3.0 Total granulate 1113.6 81.9 Microcrystalline cellulose
144.4 10.6 PH102 Crospovidone 68.0 5.0 Colloidal silicon dioxide
6.8 0.5 Sodium stearyl fumarate 27.2 2.0 Total 1360.0 100.0
[0108] The tablets are characterized by the following parameters:
Hardness 180-260 N; friability 0.3%; disintegration <45 sec.
[0109] (e) Coating process:
TABLE-US-00005 TABLE 5 Substance gr % HPMC based coating 150 15
Purified Water 850 85 Total 1000 100
[0110] 1,000 gr tablets were charged into a fully perforated pan
coater. The coating solution was applied onto the tablets using
spray coating. When a weight gain of 2-5 wt % was reached, the
tablets were dried.
Coating parameters: Inlet air temp: 45-60.degree. C. Outlet air
temp: 32-40.degree. C.
Pan RPM: 6-12
[0111] Air flow: 100-200 cfm Nozzle diameter: 0.8 mm
Atomizing air: 0.8-1.5 bar
[0112] * Coating adds 2-5% to the weight of the core (1,360
mg).
Example 5: In Vitro Dissolution Test
[0113] Dissolution testing was conducted to the pharmaceutical
composition prepared according to Example 4. The following
conditions were used: [0114] Dissolution instrument: Distek
Evolution 6100 [0115] Medium: pH 4.0 McIlvaine buffer [0116]
Apparatus USP: Apparatus II (paddle method); 100 rpm [0117]
Temperature: 37.degree. C..+-.0.5.degree. C. [0118] Time: Samples
taken at 15 minutes [0119] UV-VIS Instrument: Agilent 8453 UV-VIS;
360 nm with 600 nm background [0120] The dissolution result for the
tablets obtained after applying the ferric citrate solution onto
inert cores (Example 4) was 98% dissolution in 15 min
[0121] As can be seen from the dissolution result, the ferric
citrate tablets obtained after applying the ferric citrate solution
onto inert cores (Example 4) showed a surprising higher dissolution
rate than the reference ferric citrate tablets (Examples 1 and
2).
Example 6: BET Surface Area Analysis
[0122] A BET analysis was conducted according to the standards set
forth in the United States Pharmacopeia (USP), the results of which
are depicted in Table 6:
TABLE-US-00006 TABLE 6 BET active surface Product area results
(m.sup.2/g) Milled coated granules 2.745 (inert core coated with
ferric citrate and a binder)
Example 7: Process for Preparing Ferric Citrate Tablets According
to Embodiments of the Present Invention
[0123] (a) Preparing the granules:
[0124] 0.601 kg of ferric citrate and 0.024 kg PVP K-30/povidone
were dissolved in 1.202 Liter of hot purified water (80.degree. C.)
to attain a visually clear solution. The solution was then applied
onto pre-heated 0.541 kg of AVICEL.RTM. 101/microcrystalline
cellulose using spray coating in fluid bed coater GLATT GPCG-1.
Additional clear solutions containing 0.601 kg of ferric citrate
and 0.024 kg PVP K-30/povidone dissolved in 1.202 Liter hot
purified water (80.degree. C.) were repeatedly applied onto the
thus formed granules until gaining a ferric citrate content of at
least 80%. To avoid solidification of the product, the solution was
kept heated above 80.degree. C. and stirred throughout the
process.
[0125] Process parameters:
[0126] Inlet air temp: 40-60.degree. C.
[0127] Product temp: 30-40.degree. C.
[0128] Outlet air temp: 35-45.degree. C.
[0129] Solution rate: 3-10 g/min
[0130] Nozzle diameter: 1.0 mm
[0131] Atomizing pressure: 1-2 bar
[0132] (b) Milling:
[0133] The final granules were milled using Clit mill with 500
micron sieve to form a powder. The mean particle size measured was
less than about 400 microns. Furthermore, about 50% of the
particles had a particle size of less than about 75 microns.
[0134] (c) Blending the milled granules with pharmaceutically
acceptable excipients:
[0135] The following substances were homogenously blended (Table
7):
TABLE-US-00007 TABLE 7 Substance gr Milled Ferric citrate granules
1000.0 AVICEL .RTM. 102/microcrystalline 40.2 cellulose
Crospovidone (Kollidon CL) 85.2 PVP K-30 60.8 Silicon
dioxide/colloidal silicon 6.1 dioxide Sodium stearyl fumarate
24.3
[0136] (d) Tableting:
[0137] The blend from (c) was compressed into 1,406 mg tablets,
with the following composition (Table 8):
TABLE-US-00008 TABLE 8 Substance mg/tab % Granulate: Ferric citrate
1054.5 75.0 Microcrystalline cellulose 4.3 0.3 PH101 Povidone K 30
50.8 3.6 Total granulate: 1109.6 78.9 Microcrystalline cellulose
43.6 3.1 PH102 Crospovidone (Kollidon 94.2 6.7 CL) PVP K-30 125.1
8.9 Silicon dioxide/colloidal 7.0 0.5 silicon dioxide Sodium
stearyl fumarate 26.7 1.9 Total 1406.2 100
[0138] The tablets are characterized by the following parameters:
Hardness 100-130 N; friability 0.4%; disintegration <30 min
Example 8: In Vitro Dissolution Test
[0139] Dissolution testing was conducted to the pharmaceutical
composition prepared according to Example 7. The following
conditions were used: [0140] Dissolution instrument: VanKel SN
1-3148-1093 [0141] Medium: pH 4.0 McIlvaine buffer [0142] Apparatus
USP: Apparatus II (paddle method); 100 rpm [0143] Temperature:
37.degree. C. .+-.0.5.degree. C. [0144] Time: Samples taken at 15
minutes [0145] UV-VIS Instrument: Agilent 8453 UV-VIS; 360 nm
[0146] The dissolution result for the tablets obtained after
applying the ferric citrate solution onto inert cores (Example 7)
was 96% dissolution in 15 min
[0147] As can be seen from the dissolution result, the ferric
citrate tablets obtained after applying the ferric citrate solution
onto inert cores (Example 7) showed a surprising higher dissolution
rate than the reference ferric citrate tablets (Examples 1 and
2).
Example 9: Stability Test
[0148] Tablets prepared according to Example 7 were placed in
stability testing in 2 conditions: A) accelerated conditions
(40.degree. C., 75% relative humidity), and B) room temperature
conditions (25.degree. C., 60% relative humidity). In particular,
tablets were packaged in aluminum blisters which were stored at the
different storage conditions for a total of 3 months. Few blisters
were taken out of the accelerated conditions incubator at three
time points: 1 month, 2 months and 3 months. Blisters were taken
out of the room temperature conditions incubator at 3 months. The
dissolution profile of the tablets was determined as described
hereinabove. Results showed that the formulation of the present
invention was stable under conditions tested, with dissolution
higher than 90% after 15 min in all storage conditions.
[0149] While certain embodiments of the invention have been
illustrated and described, it will be clear that the invention is
not limited to the embodiments described herein. Numerous
modifications, changes, variations, substitutions and equivalents
will be apparent to those skilled in the art without departing from
the spirit and scope of the present invention as described by the
claims, which follow.
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