U.S. patent application number 17/198013 was filed with the patent office on 2022-02-24 for pharmaceutical formulations of a hif hydroxylase inhibitor.
The applicant listed for this patent is FibroGen, Inc.. Invention is credited to David Conca, Lee Allen Flippin, Scott David Leigh, Claudia Witschi, Lee Robert Wright.
Application Number | 20220054474 17/198013 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-24 |
United States Patent
Application |
20220054474 |
Kind Code |
A1 |
Conca; David ; et
al. |
February 24, 2022 |
PHARMACEUTICAL FORMULATIONS OF A HIF HYDROXYLASE INHIBITOR
Abstract
The present disclosure relates to pharmaceutical formulations of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid and methods of use thereof.
Inventors: |
Conca; David; (San
Francisco, CA) ; Flippin; Lee Allen; (Woodside,
CA) ; Leigh; Scott David; (Castro Valley, CA)
; Witschi; Claudia; (San Francisco, CA) ; Wright;
Lee Robert; (Redwood City, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FibroGen, Inc. |
San Francisco |
CA |
US |
|
|
Appl. No.: |
17/198013 |
Filed: |
March 10, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16983991 |
Aug 3, 2020 |
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17198013 |
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16035503 |
Jul 13, 2018 |
10765672 |
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16983991 |
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14896353 |
Dec 4, 2015 |
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PCT/US2014/041021 |
Jun 5, 2014 |
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16035503 |
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61831909 |
Jun 6, 2013 |
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International
Class: |
A61K 31/472 20060101
A61K031/472; A61K 9/28 20060101 A61K009/28; A61K 9/48 20060101
A61K009/48; A61K 9/20 20060101 A61K009/20 |
Claims
1. A pharmaceutical composition formulated to prevent or reduce the
photodegradation of an active ingredient
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, the composition comprising the active ingredient
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, and an effective amount of a photostabilizing agent, which
photostabilizing agent: i) prevents the transmission of light at a
wavelength range of between about 200 nm and 550 nm; and ii) is
admixed with the active ingredient, or provided in an outer coating
or shell surrounding the active ingredient, such that the
composition upon exposure to light contains less than about 0.2%
w/w photodegradation product of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid relative to the amount of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
2. The pharmaceutical composition of claim 1, wherein the
photostabilizing agent comprises titanium dioxide and at least one
additional dye selected from the group consisting of a red dye, a
yellow dye, and a combination of a red dye and a yellow dye.
3. The pharmaceutical composition of claim 1, wherein the
photostabilizing agent comprises titanium dioxide and at least one
additional dye selected from the group consisting of iron oxide
red, Allura Red AC, Allura Red AC Aluminum Lake, iron oxide yellow,
Sunset Yellow FCF, and Sunset Yellow FCF Aluminum Lake, or a
combination thereof.
4. The pharmaceutical composition of claim 1, comprising from about
20 mg to about 200 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
5. The pharmaceutical composition of claim 1, comprising about 20
mg, about 50 mg, or about 100 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
6. A solid dosage form comprising the pharmaceutical composition of
claim 1, wherein the solid dosage form is selected from capsule,
tablet, bead, granule, pellet, lozenge, pill, or gum.
7. The solid dosage form of claim 6, wherein the solid dosage form
is tablet or capsule.
8. A tablet comprising the pharmaceutical composition of claim 1,
wherein (i) the photostabilizing agent is admixed with the active
ingredient; or (ii) the tablet comprises a tablet core and a
coating and the photostabilizing agent is admixed with the active
ingredient in the tablet core; or (iii) the tablet comprises a
tablet core and a coating and the tablet core comprises the active
ingredient, and the coating comprises the photostabilizing
agent.
9. The tablet of claim 8, wherein the tablet comprises a tablet
core and a coating and the tablet core comprises the active
ingredient, and the coating comprises the photostabilizing agent,
and further wherein the photostabilizing agent comprises at least
about 0.1 mg/cm.sup.2 titanium dioxide and at least one additional
dye selected from the group consisting of: at least about 0.1
mg/cm.sup.2 Allura Red AC; at least about 0.1 mg/cm.sup.2 Allura
Red AC in aluminum lake; at least about 0.004 mg/cm.sup.2iron oxide
red; at least about 0.009 mg/cm.sup.2iron oxide yellow; at least
about 0.01 mg/cm.sup.2Sunset Yellow FCF; and at least about 0.01
mg/cm.sup.2Sunset Yellow FCF in aluminum lake; wherein the amount
of photostabilizing agent is based on surface area of the tablet
core.
10. The tablet of claim 8, wherein the tablet comprises a tablet
core and a coating and the tablet core comprises the active
ingredient, and the coating comprises the photostabilizing agent,
and further wherein the photostabilizing agent comprises, from
about 0.1 to about 2 mg/cm.sup.2 titanium dioxide and at least one
additional dye selected from the group consisting of: from about
0.1 to about 0.4 mg/cm.sup.2 Allura Red AC; from about 0.1 to about
0.4 mg/cm.sup.2 Allura Red AC in aluminum lake; from about 0.004 to
about 0.4 mg/cm.sup.2 iron oxide red; from about 0.009 to about 0.2
mg/cm.sup.2 iron oxide yellow; from about 0.01 to 0.03 mg/cm.sup.2
Sunset Yellow FCF; and from about 0.01 to 0.03 mg/cm.sup.2 Sunset
Yellow FCF in aluminum lake; wherein the amount of photostabilizing
agent is based on surface area of the tablet core.
11. The tablet of claim 8, wherein the tablet comprises a tablet
core and a coating and the tablet core comprises
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, and the coating comprises the photostabilizing agent, and the
coating is present in an amount from about 3% to about 8% w/w
(based on the weight of the tablet core).
12. The tablet of claim 11, wherein the photostabilizing agent
comprises titanium dioxide and Allura Red AC aluminum lake.
13. The tablet of claim 12, wherein the coating comprises from
about 0.1 to about 0.4 mg/cm.sup.2 titanium dioxide and from about
0.1 to about 0.4 mg/cm.sup.2 Allura Red AC in aluminum lake, and
wherein the amount of titanium dioxide and Allura Red AC in
aluminum lake is based on surface area of the tablet core.
14. The tablet of claim 13, wherein the tablet core comprises about
20 mg, about 50 mg or about 100 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
photostabilizing agent comprises 0.1 to about 0.4 mg/cm.sup.2
titanium dioxide and from about 0.1 to about 0.4 mg/cm.sup.2 Allura
Red AC in aluminum lake wherein the amount of titanium dioxide and
Allura Red AC in aluminum lake is based on surface area of the
tablet core.
15. A capsule comprising the pharmaceutical composition of claim 1,
wherein the capsule comprises a capsule fill and a capsule shell,
and further wherein the capsule fill comprises an active ingredient
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]acetic
acid, and a pharmaceutically acceptable excipient, and the capsule
shell comprises an effective amount of a photostabilizing
agent.
16. The capsule of claim 15, wherein the capsule shell comprises
from about 1.8% to about 6%, or from about 2% to about 3.5%, w/w
photostabilizing agent (based on the weight of the capsule
shell).
17. The capsule of claim 15, wherein the photostabilizing agent
comprises titanium dioxide and at least one additional dye selected
from the group consisting of iron oxide red, Allura Red AC, and
iron oxide yellow, or a combination thereof.
18. A method of inhibiting the photodegradation of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3carbonyl)-amino]-acetic
acid, said method comprising formulating
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid with an effective amount of a photostabilizing agent.
19. The method of claim 18, wherein the photostabilizing agent
comprises titanium dioxide and at least one additional dye selected
from the group consisting of a red dye, a yellow dye, and a
combination of a red dye and a yellow dye.
20. The method of claim 18, wherein the photostabilizing agent
comprises titanium dioxide and at least one additional dye selected
from the group consisting of iron oxide red, Allura Red AC, Allura
Red AC Aluminum Lake, iron oxide yellow, Sunset Yellow FCF, and
Sunset Yellow FCF Aluminum Lake, or a combination thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/983,991, filed Aug. 3, 2020, which is a continuation of U.S.
application Ser. No. 16/035,503, filed Jul. 13, 2018, now U.S. Pat.
No. 10,765,672, which is a continuation of U.S. application Ser.
No. 14/896,353, filed Dec. 4, 2015, now abandoned, which is a U.S.
National Stage Application under 35 U.S.C. .sctn. 371 of
International Application No. PCT/US2014/041021, filed Jun. 5,
2014, which claims the benefit under 35 U.S.C. .sctn. 119(e) of
U.S. Provisional Application No. 61/831,909, filed Jun. 6, 2013,
all of which are incorporated herein by reference in their
entireties.
BACKGROUND
[0002] The present invention relates generally to pharmaceutical
formulations of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
[0003]
[(4-Hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acet-
ic acid (alternatively referred to herein as Compound A) is a
potent inhibitor of hypoxia inducible factor (HIF) prolyl
hydroxylase, as described in U.S. Pat. No. 7,323,475. HIF prolyl
hydroxylase inhibitors are useful for increasing the stability
and/or activity of HIF, and useful for, inter alia, treating and
preventing disorders associated with HIF, including anemia, and
ischemia- and hypoxia-related disorders.
[0004] It has recently been discovered that Compound A undergoes
decomposition after exposure to light. Heretofore, pharmaceutical
formulations of Compound A which provide the necessary
photostability of the compound have not yet been taught.
SUMMARY
[0005] The present disclosure fulfills the need of providing
photostability of Compound A and others by providing a
pharmaceutical formulation comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, a pharmaceutically acceptable excipient and an effective
amount of a photostabilizing agent. In one embodiment, the
pharmaceutical formulation comprises less than about 0.2% w/w
(based on the amount of active pharmaceutical ingredient ("API"))
photodegradation product of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In another embodiment, the photostabilizing agent blocks
light at a wavelength range of between about 200 and about 550
nm.
[0006] In one embodiment, the photostabilizing agent comprises
titanium dioxide and at least one additional dye. In one
embodiment, the photostabilizing agent blocks light at a wavelength
range of between about 200 and about 550 nm. In one embodiment, the
dye is selected from the group consisting of a black dye, a blue
dye, a green dye, a red dye, an orange dye, a yellow dye, and
combinations thereof. In another embodiment, the dye is selected
from the group consisting of a red dye, an orange dye, a yellow
dye, and combinations thereof.
[0007] In one embodiment, the dye is selected from the group
consisting of Allura Red AC, Allura Red AC aluminum lake, iron
oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow FCF
aluminum lake, Indigotine, Indigotine aluminum lake, and
combinations thereof.
[0008] In one embodiment, the pharmaceutical formulation comprises
from about 20 mg to about 200 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In another embodiment, the pharmaceutical formulation
comprises about 20 mg, about 50 mg, or about 100 mg of [
(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
[0009] In one embodiment, a solid dosage form comprises the
pharmaceutical formulation and the solid dosage form is selected
from a capsule, tablet, bead, granule, pellet, lozenge, pill, or
gum. In another embodiment, the solid dosage form is a tablet. In
another embodiment, the solid dosage form is a capsule.
[0010] The present disclosure provides a tablet comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, a pharmaceutically acceptable excipient and an effective
amount of a photostabilizing agent. In one embodiment, the tablet
comprises a tablet core and a coating. In some embodiments, the
photostabilizing agent is blended into the tablet or the tablet
core. In other embodiments, the tablet core comprises
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid and the pharmaceutically acceptable excipient, and the coating
comprises the photostabilizing agent.
[0011] In one embodiment, the coating is present in the tablet in
an amount that is from about 3% to about 8% w/w based on the weight
of the tablet core. In another embodiment, the tablet core
comprises from about 22% to about 28% w/w
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid (based on the weight of the tablet core). In yet another
embodiment, the pharmaceutically acceptable excipient comprises
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate.
[0012] In one embodiment, the coating comprises from about 0.1% to
about 50% w/w photostabilizing agent (based on coating weight). In
some embodiments, the photostabilizing agent comprises titanium
dioxide and at least one additional dye selected from the group
consisting of Allura Red AC, Allura Red AC aluminum lake, iron
oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow FCF
aluminum lake, Indigotine, Indigotine aluminum lake, and
combinations thereof. In another embodiment, the photostabilizing
agent comprises titanium dioxide and Allura Red AC aluminum
lake.
[0013] The present disclosure provides a capsule comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, a pharmaceutically acceptable excipient and an effective
amount of a photostabilizing agent. In one embodiment, the capsule
comprises a capsule fill and a capsule shell. In one embodiment,
the capsule fill comprises
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]--
acetic acid and the pharmaceutically acceptable excipient, and the
capsule shell comprises the photostabilizing agent.
[0014] In one embodiment, the capsule fill comprises from about 12%
to about 15% w/w
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid (based on the weight of the capsule fill). In another
embodiment, the pharmaceutically acceptable excipient comprises
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate.
[0015] In one embodiment, the capsule shell comprises the
photostabilizing agent in an amount of from about 1.8% to about 6%
w/w (based on the weight of the capsule shell). In some
embodiments, the photostabilizing agent comprises titanium dioxide
and at least one additional dye selected from the group consisting
of Allura Red AC, iron oxide red, iron oxide yellow, and
combinations thereof.
[0016] In a separate embodiment, a method of inhibiting the
photodegradation of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid is provided. The method comprises formulating
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid with an effective amount of a photostabilizing agent. In
another embodiment, the photostabilizing agent comprises titanium
dioxide and at least one additional dye.
[0017] In yet another embodiment, a method for treating,
pretreating, or delaying onset or progression of a condition
mediated at least in part by hypoxia inducible factor (HIF) is
provided. The method comprises administering to a patient in need
thereof, a pharmaceutical formulation, a tablet, or a capsule as
described herein.
[0018] In still yet another embodiment, a method for treating,
pretreating, or delaying onset or progression of anemia is
provided. The method comprises administering to a patient in need
thereof, a pharmaceutical formulation, a tablet, or a capsule as
described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 illustrates the HPLC chromatograms of Compound A
powders before and after exposure to sunlight. See Example 1 for
details.
[0020] FIGS. 2A and 2B illustrates the amount of photodegradation
product in tablets containing either 20 mg (FIG. 2A) or 100 mg
(FIG. 2B) of Compound A upon light exposure. The tablets are coated
with a coating formula containing Allura Red AC/Indigotine/titanium
dioxide (labeled as Allura Red AC/Indigotine in figures), Allura
Red AC/titanium dioxide (labeled as Allura Red AC in figures), or
red iron oxide/titanium dioxide (labeled as Red Iron Oxide in
figures). See Example 2 for details.
[0021] FIGS. 3A and 3B illustrates the amount of photodegradation
product in tablets containing either 20 mg (FIG. 3A) or 100 mg
(FIG. 3B) of Compound A upon light exposure. The tablets are coated
with a variety of pink/peach coating formulas. See Example 2 for
details.
[0022] FIG. 4 demonstrates the amount of photodegradation product
in capsules covered with gelatin films containing various
photostabilizing agents upon light exposure. See Example 3 for
details.
DETAILED DESCRIPTION
Definitions
[0023] As used herein, the following terms have the following
meanings.
[0024] The singular forms "a," "an," and "the" and the like include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes both a single
compound and a plurality of different compounds.
[0025] The term "about" when used before a numerical designation,
e.g., temperature, time, amount, and concentration, including a
range, indicates approximations which may vary by .+-.10%, .+-.5%
or .+-.1%.
[0026] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods, devices, and materials are now
described. All publications cited herein are incorporated herein by
reference in their entirety for the purpose of describing and
disclosing the methodologies, reagents, and tools reported in the
publications that might be used in connection with the invention.
Nothing herein is to be construed as an admission that the
invention is not entitled to antedate such disclosure by virtue of
prior invention.
[0027] The practice of the present invention will employ, unless
otherwise indicated, conventional methods of chemistry,
biochemistry, molecular biology, cell biology, genetics,
immunology, and pharmaceutical sciences, within the skill of the
art. Such techniques are explained fully in the literature. (See,
e.g., Gennaro, A. R., ed. (1990) Remington's Pharmaceutical
Sciences, 18.sup.th ed., Mack Publishing Co.; Colowick, S. et al.,
eds., Methods In Enzymology, Academic Press, Inc.; D. M. Weir, and
C. C. Blackwell, eds. (1986) Handbook of Experimental Immunology,
Vols. I-IV, Blackwell Scientific Publications; Maniatis, T. et al.,
eds. (1989) Molecular Cloning: A Laboratory Manual, 2.sup.nd
edition, Vols. I-III, Cold Spring Harbor Laboratory Press; Ausubel,
F. M. et al., eds. (1999) Short Protocols in Molecular Biology,
4.sup.th edition, John Wiley & Sons; Ream et al., eds. (1998)
Molecular Biology Techniques: An Intensive Laboratory Course,
Academic Press; Newton & Graham eds. (1997) PCR (Introduction
to Biotechniques Series), 2nd ed., Springer Verlag; European
Pharmacopoeia (Ph. Eur.), 7.sup.th edition; The United States
Pharmacopeia (USP) and the National Formulary (NF), USP 35-NF
30.
[0028] The term "API" is the abbreviation for "active
pharmaceutical ingredient." As used herein, API refers to Compound
A, or
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
[0029] The term "block light" refers to preventing or reducing the
transmittance of light by absorbing, reflecting, refracting,
diffracting, dispersing, and/or scattering light. When a dye blocks
light at a certain wavelength range, the dye prevents or reduces
the transmittance of light at that wavelength range by absorbing,
reflecting, refracting, diffracting, dispersing, and/or scattering
light.
[0030] The term "capsule" refers to a solid dosage form of a
pharmaceutical formulation that comprises a capsule shell and a
capsule fill.
[0031] The term "capsule fill" refers to the material enclosed
within a capsule shell. Typically, the capsule fill comprises the
active pharmaceutical ingredient (API) and one or more
pharmaceutically acceptable excipients. The amount of API in the
capsule fill can be expressed as a weight percent of API based on
the total weight of the capsule fill (w/w %).
[0032] The term "capsule shell" refers to an outer layer of a
capsule. The capsule shell comprises gelatin, cellulose polymers or
other suitable materials which would allow for delivery of the API.
The capsule shell may be a hard-shell consisting of a telescoping
cap and body piece in a range of standard sizes. The cap and body
piece may be sealed after addition of the capsule fill. Such
hard-shelled capsules are typically used to deliver dry, powdered
API in the capsule fill. The capsule shell may be a one-piece
soft-shell used to deliver API as a solution or suspension in the
capsule fill. In one embodiment, the capsule shell may comprise the
photostabilizing agent. The amount of photostabilizing agent in the
capsule shell can be expressed as a weight percent of
photostabilizing agent based on the total weight of the capsule
shell (% w/w). In one embodiment, the capsule shell comprises
gelatin (a gelatin shell). In another embodiment, the capsule shell
comprises hydroxypropylmethylcellulose (HPMC) (an HPMC shell).
[0033] The term "dye" as used throughout, includes true dyes (as
defined in color and dye chemistry), dye lakes and pigments. A true
dye (as defined in color and dye chemistry) is a colored substance
(including white color) that is soluble in water and/or an organic
solvent and has an affinity to the substrate to which it is being
applied such that color is imparted to the substrate. A dye lake is
a solid, water insoluble form of a true dye. It is manufactured by
mixing a true dye with an inert material such as aluminum hydroxide
(aluminum lake, commonly used), barium sulfate, calcium sulfate,
aluminum oxide (alumina). The amount of true dye in the lake is
expressed as "dye strength." A pigment is a colored substance that
is insoluble in water or organic solvent.
[0034] Dyes appear in colors because they absorb light in the
visible spectrum (400-700 nm) and transmit, reflect or scatter
light of other wavelengths in the visible spectrum. A "yellow dye"
absorbs predominantly blue light and appears yellow in color. An
"orange dye" absorbs predominantly green-blue light and appears
orange in color. A "red dye" absorbs predominantly blue-green light
and appears red in color. A "blue dye" absorbs predominantly yellow
light and appears blue in color. A "green dye" predominantly
absorbs red and orange light and appears green in color. A "black
dye" absorbs light of the entire visible spectrum and appears black
in color. Examples of red dye, yellow dye, green dye, blue dye and
black dye are given in the following table. In addition to
absorbing light, these dyes may block light through reflecting,
refracting, diffracting, dispersing, and/or scattering light.
[0035] Different colors can also be obtained by mixing two or more
dyes. For example, orange dyes of different shades can be obtained
by mixing different amount of red and yellow dyes.
[0036] Dyes described in this application are referred to by their
principal name. One of skill in the art would be able to readily
ascertain the dye's US name or C.I. name (Color Index name).
Non-limiting examples of dyes are listed in the following
table.
TABLE-US-00001 Color Principal Name US Name C.I. Name White dye
Titanium dioxide C.I. Pigment White 6 Beige dye Caramel C.I.
Natural Brown 10 Red dye Allura Red or FD&C Red 40 C.I. Food
Red 17 Allura Red AC Red dye Amaranth C.I. Food Red 9 Red dye
Anthocyanin Red dye Azorubine C.I. Food Red 3 Red dye Beetroot Red
Red dye Canthaxanthin C.I. Food Orange 8 Red dye Carmine C.I.
Natural Red 4 Red dye D&C Red 33 D&C Red 33 C.I. Food Red
12 Red dye Eosine YS D&C Red 22 C.I. Food Red 87 Red dye
Erythrosine FD&C Red 3 (dye only) C.I. Food Red 14 Red dye Iron
oxide red or C.I. Pigment Red 101 & Red iron oxide 102 Red dye
Lithol Rubine BK D&C Red 7 Red dye Phloxine B D&C Red 28
Red dye Ponceau 4R C.I. Food Red 7 Red dye Red 2G C.I. Food Red 10
Yellow dye Beta-Carotene C.I. Food Orange 5 Yellow dye Mixed
Carotenes C.I. Food Orange 5 Yellow dye Curcumin C.I. Natural
Yellow 3 Yellow dye D&C Yellow 10 D&C Yellow 10 C.I. Food
Yellow 13 Yellow dye Iron oxide yellow or C.I. Pigment Yellow
Yellow iron oxide 42&43 Yellow dye Quinoline Yellow WS C.I.
Food Yellow 13 Yellow dye Riboflavin Yellow dye Sunset Yellow FCF
FD&C Yellow 6 C.I. Food Yellow 3 Yellow dye Tartrazine FD&C
Yellow 5 C.I. Food Yellow 4 Green dye Chlorophylls and C.I. Natural
Green 3 Chlorophyllins Green dye Cu Complexes of C.I. Natural Green
3 Chlorophylls and Chlorophyllins Green dye Fast Green FCF FD&C
Green 3 C.I. Food Green 3 Green dye Green S C.I. Food Green 4 Blue
dye Brilliant Blue FCF FD&C Blue 1 C.I. Food Blue 2 Blue dye
Indigotine FD&C Blue 2 C.I. Food Blue 1 Blue dye Patent Blue V
C.I. Food Blue 5 Black dye Brilliant Black BN C.I. Food Black 1
Black dye Iron oxide black C.I. Pigment Black 11 (or Black iron
oxide) Black dye Vegetable Carbon C.I. Food Black 3
[0037] The term "pharmaceutically acceptable" indicates that the
material does not have properties that would cause one of skill in
the art to avoid administration of the material to a patient,
taking into consideration the disease or conditions to be treated
and the respective route of administration. Further, the material
is considered to be safe for administration in humans or
animals.
[0038] The term "excipient" or "pharmaceutically acceptable
excipient" refers to pharmacologically inactive substances that are
added to a pharmaceutical preparation in addition to the active
pharmaceutical ingredient. Excipients may take the function of
vehicle, diluent, release, disintegration or dissolution modifying
agent, absorption enhancer, stabilizer or a manufacturing aid among
others. Excipients may include fillers (diluents), binders,
disintegrating agents, lubricants, and glidants. Examples of
excipient classes frequently used are listed below.
[0039] "Diluent or filler" refers to substances that are used to
dilute the active pharmaceutical ingredient prior to delivery.
Diluents can also serve as stabilizers. Non-limiting examples of
diluents include starch, saccharides, disaccharides, sucrose,
lactose, polysaccharides, cellulose, cellulose ethers,
hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol,
maltitol, microcrystalline cellulose, calcium or sodium carbonate,
lactose, lactose monohydrate, dicalcium phosphate, cellulose,
compressible sugars, dibasic calcium phosphate dehydrate, mannitol,
microcrystalline cellulose, and tribasic calcium phosphate.
[0040] "Binder" refers to any pharmaceutically acceptable substance
which can be used to bind the active and inert components together
to maintain cohesive and discrete portions. Non-limiting examples
of binders include hydroxypropylcellulose,
hydroxypropylmethylcellulose, povidone, and ethyl cellulose.
[0041] "Disintegrant or disintegrating agents" refers to a
substance which, upon addition to a solid preparation, facilitates
its break-up or disintegration after administration and permits the
release of an active ingredient as efficiently as possible to allow
for its rapid dissolution. Non-limiting examples of disintegrants
include maize starch, sodium starch glycolate, croscarmellose
sodium, crospovidone, microcrystalline cellulose, modified corn
starch, sodium carboxymethyl starch, povidone, pregelatinized
starch, and alginic acid.
[0042] "Lubricant" refers to an excipient which is added to a
powder blend to prevent the compacted powder mass from sticking to
the equipment during the tableting or encapsulation process. It
aids the ejection of the tablet form the dies, and can improve
powder flow. Non-limiting examples of lubricants include magnesium
stearate, stearic acid, silica, fats, calcium stearate,
polyethylene glycol, sodium stearyl fumarate, talc, or fatty acids
including lauric acid, oleic acid, and C.sub.8/C.sub.10 fatty
acid.
[0043] "Glidant" as used herein is intended to mean agents used in
tablet and capsule formulations to improve flow-properties during
tablet compression and to produce an anti-caking effect.
Non-limiting examples of glidants include colloidal silicon
dioxide, talc, fumed silica, starch, starch derivatives, and
bentonite.
[0044] The term "formulate" or "formulating" refers to combining
the active pharmaceutical ingredient with one or more other
components, for example, including without limitation one or more
pharmaceutically acceptable excipients, stabilizing agents,
photostabilizing agents, coatings, capsule shells, etc., in a
process, which produces a final medicinal product. Examples of
medicinal product include, but not limited to, tablets, pills,
dragees, capsules, gels, syrups, slurries, suspensions, aerosol
sprays, and solutions for injection.
[0045] The term "gelatin" refers to a solid substance derived from
collagen and can be obtained from various animal by-productions. It
is commonly used as a gelling agent in pharmaceuticals.
[0046] The term "light exposure", refers any light exposure,
including sunlight (or natural light), indoor light and exposure to
light under International Conference of Harmonization (ICH)
conditions. "ICH light exposure" means exposure to light under ICH
conditions, which may be ICH Option 1 or ICH Option 2. Under ICH
conditions, the samples are exposed to light providing an overall
illumination of not less than 1.2 million lux hours and an
integrated near ultraviolet energy of not less than 200 watt
hours/square meter, using one of the two options described below as
light sources (ICH Q1B). [0047] a. ICH Option 1: [0048] Any light
source that is designed to produce an output similar to the
D65/ID65 emission standard such as an artificial daylight
fluorescent lamp combining visible and ultraviolet (UV) outputs,
xenon, or metal halide lamp D65 is the internationally recognized
standard for outdoor daylight as defined in ISO 10977 (1993). ID65
is the equivalent indoor indirect daylight standard. For a light
source emitting significant radiation below 320 nanometers (nm), an
appropriate filter(s) may be fitted to eliminate such radiation.
[0049] b. ICH Option 2: [0050] A cool white fluorescent lamp
designed to produce an output similar to that specified in ISO
10977 (1993); and [0051] A near UV fluorescent lamp having a
spectral distribution from 320 nm to 400 nm with a maximum energy
emission between 350 nm and 370 nm; a significant proportion of UV
should be in both bands of 320 to 360 nm and 360 to 400 nm.
[0052] The term "photostabilizing agent" is an agent that prevents
or reduces the photodegradation or photodecomposition of a molecule
upon exposure to light (light under ICH condition, sunlight, indoor
light, etc.). In other words, the photostabilizing agent functions
to prevent or reduce the formation of photodegradation products.
Typically, the photostabilizing agent prevents or reduces the
photodegradation of the light-sensitive molecule by blocking the
exposure of the molecule to light within a wavelength range.
Non-limiting examples of photostabilizing agents include pigments,
dyes, dye lakes, and the like.
[0053] The term "photodegradation" and "photodecomposition" are
used interchangeably throughout the disclosure.
[0054] The term "effective amount" of a photostabilizing agent
refers to the amount of a photostabilizing agent in a
pharmaceutical formulation that is sufficient to prevent or reduce
the photodegradation of the active pharmaceutical ingredients
(API), such that the amount of photodegradation product(s) that is
produced is limited to a desired maximum level under specified
light conditions. In the embodiments described herein, the
effective amount of a photostabilizing agent is the amount
sufficient to limit the amount of photodegradation product of
Compound A that is produced to a level that is less than about 0.2%
w/w Compound A (or 2000 ppm), under ICH conditions. In some
embodiments, the effective amount of photostabilizing agent may
limit the amount of photodegradation product of Compound A that is
produced to a level that is less than about 0.15% w/w Compound A,
less than about 0.1% w/w Compound A, or less than 0.05% w/w
Compound A. As will be apparent to one skilled in the formulations
art, the effective amount of a stabilizing agent will vary with the
particular agent used. Using the disclosure herein, particularly
the analytical methods described in the examples, and the general
knowledge in the formulations art, one of ordinary skill in the art
can readily determine the amount of any particular agent (or
combination of agents) that will achieve the level of
photoprotection (i.e., reduction of the production of
photodegradation product) sufficient to limit photodegradation
product to the desired maximum level.
[0055] The term "photodegradation product" as used herein refers to
a new molecule that is formed from Compound A upon exposing
Compound A to light. The photodegradation product may be detected
by a variety of standard analytical methods (e.g., high-performance
liquid chromatography (HPLC), liquid chromatography-mass
spectrometry (LC-MS), gas chromatography (GC), nuclear magnetic
resonance (NMR), Fourier transform infrared spectroscopy (FTIR),
etc.). In one embodiment, the photodegradation product may be
detected and measured by HPLC, as further described in Example
1.
[0056] The term "tablet" refers to a solid dosage form of a
pharmaceutical formulation in which the API is blended with one or
more pharmaceutically acceptable excipient and compressed into a
single solid final dosage form. Tablets can be produced in a wide
variety of sizes, shapes, and surface markings Tablets may be
uncoated or coated by a variety of techniques that are well known
in the art. Typically, a tablet comprises a tablet core and a
coating.
[0057] The term "tablet core" refers to the inner part of a tablet
containing the API and one or more pharmaceutically acceptable
excipient compressed into the desired shape but not including the
coating. The amount of API in the tablet core can be expressed as a
percent of API by weight based on the total weight of the tablet
core, % w/w.
[0058] The term "coating" refers to an outer part of a tablet. For
tablets as described herein, the coating is applied to the outer
surface of the tablet core and typically adheres thereto. The
coating may provide one or more of the following properties: taste
masking, protecting the API(s) from photodegradation, ease of
administration, release modification of the API(s), dust
protection, or unique appearance (colors), among other things.
Non-limiting examples of coating materials include
polyvinylalcohol-based compounds, hydroxyethylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose sodium,
polyethylene glycol 4000 and cellulose acetate phthalate. In one
embodiment, the coating is a polyvinylalcohol-based coating. The
amount of coating that is applied over the outer surface of tablet
core can be expressed as a percent of coating by weight based on
the weight of the tablet core, % w/w. In one embodiment, the
coating may comprise a photostabilizing agent such as a dye. The
amount of dye within a coating can be expressed as a percent of dye
weight based on the weight of the coating % w/w. Alternatively, the
amount of dye within a coating can be expressed as the amount of
the dye applied per surface area unit of the tablet core,
mg/cm.sup.2.
[0059] The term "anemia" as used herein refers to any abnormality
in hemoglobin or erythrocytes that leads to reduced oxygen levels
in the blood. Anemia can be associated with abnormal production,
processing, or performance of erythrocytes and/or hemoglobin. The
term anemia refers to any reduction in the number of red blood
cells and/or level of hemoglobin in blood relative to normal blood
levels. Anemia can arise due to conditions such as acute or chronic
kidney disease, infections, inflammation, cancer, irradiation,
toxins, diabetes, and surgery. Infections may be due to, e.g.,
virus, bacteria, and/or parasites, etc. Inflammation may be due to
infection, autoimmune disorders, such as rheumatoid arthritis, etc.
Anemia can also be associated with blood loss due to, e.g., stomach
ulcer, duodenal ulcer, hemorrhoids, cancer of the stomach or large
intestine, trauma, injury, surgical procedures, etc. Anemia is
further associated with radiation therapy, chemotherapy, and kidney
dialysis. Anemia is also associated with HIV-infected patients
undergoing treatment with azidothymidine (zidovudine) or other
reverse transcriptase inhibitors, and can develop in cancer
patients undergoing chemotherapy, e.g., with cyclic cisplatin- or
non-cisplatin-containing chemotherapeutics. Aplastic anemia and
myelodysplastic syndromes are diseases associated with bone marrow
failure that result in decreased production of erythrocytes.
Further, anemia can result from defective or abnormal hemoglobin or
erythrocytes, such as in disorders including microcytic anemia,
hypochromic anemia, etc. Anemia can result from disorders in iron
transport, processing, and utilization, see, e.g., sideroblastic
anemia, etc.
[0060] The terms "disorders," "diseases," and "conditions" are used
inclusively herein and refer to any condition deviating from
normal.
[0061] "Treatment", "treating", and "treat" are defined as acting
upon a disease, disorder, or condition with an agent to reduce or
ameliorate the harmful or any other undesired effects of the
disease, disorder, or condition and/or its symptoms. Treatment, as
used herein, covers the treatment of a human patient, and includes:
(a) reducing the risk of occurrence of the condition in a patient
determined to be predisposed to the disease but not yet diagnosed
as having the condition, (b) impeding the development of the
condition, and/or (c) relieving the condition, i.e., causing
regression of the condition and/or relieving one or more symptoms
of the condition.
[0062] "Administration" refers to introducing an agent into a
patient. A therapeutic amount can be administered, which can be
determined by the treating physician or the like. An oral route of
administration is preferred for Compound A. The related terms and
phrases "administering" and "administration of", when used in
connection with a compound or pharmaceutical formulation (and
grammatical equivalents) refer both to direct administration, which
may be administration to a patient by a medical professional or by
self-administration by the patient, and/or to indirect
administration, which may be the act of prescribing a drug. For
example, a physician who instructs a patient to self-administer a
drug and/or provides a patient with a prescription for a drug is
administering the drug to the patient. In any event, administration
entails delivery of the drug to the patient.
[0063] Hypoxia inducible factor (HIF) is a basic helix-loop-helix
(bHLH) PAS (Per/Arnt/Sim) transcriptional activator that mediates
changes in gene expression in response to changes in cellular
oxygen concentration. HIF is a heterodimer containing an
oxygen-regulated .alpha.-subunit (HIF.alpha.), and a constitutively
expressed .beta.-subunit (HIF.beta./ARNT). In oxygenated (normoxic)
cells, HIF.alpha. subunits are rapidly degraded by a mechanism that
involves ubiquitination by the von Hippel-Lindau tumor suppressor
(pVHL) E3 ligase complex. Under hypoxic conditions, HIF.alpha. is
not degraded, and an active HIF.alpha./.beta. complex accumulates
in the nucleus, and activates the expression of several genes
including glycolytic enzymes, glucose transporters, erythropoietin
(EPO), and vascular endothelial growth factor (VEGF). (Jiang et al.
(1996) J. Biol. Chem. 271:17771-17778; Iliopoulus et al. (1996)
Proc. Natl. Acad. Sci. USA, 93:10595-10599; Maxwell et al. (1999)
Nature 399:271-275; Sutter et al. (2000) Proc. Natl. Acad. Sci. USA
97:4748-4753; Cockman et al. (2000) J. Biol. Chem. 275:25733-25741;
and Tanimoto et al. (2000) EMBO J. 19:4298-4309.)
[0064] The terms "HIF-associated conditions" and "conditions
mediated at least in part by HIF" are used inclusively and refer to
any condition that can be associated with below normal, abnormal,
or inappropriate modulation of HIF. HIF-associated conditions
include any condition wherein an increase in HIF level would
provide therapeutic benefit. HIF-associated conditions include
anemic conditions and tissue damage or disorders associated with
ischemic or hypoxic conditions.
[0065] The terms "HIF prolyl hydroxylase", "PHD", "EGLN", and "HIF
PH" refer to any enzyme that modifies the alpha subunit of HIF
protein by hydroxylation of one or more proline residues. HIF PH
includes members of the Egl-Nine (EGLN) gene family described by
Taylor (2001, Gene 275:125-132), and characterized by Aravind and
Koonin (2001, Genome Biol 2: RESEARCH 0007), Epstein et al. (2001,
Cell 107:43-54), and Bruick and McKnight (2001, Science
294:1337-1340). HIF PH2, as used in exemplary assays described
herein (infra), may be any HIF PH2, also referred to as PHD2, e.g.,
human EGLN1 (GenBank Accession No. AAG33965; Dupuy et al. (2000)
Genomics 69:348-54), mouse EGLN1 (GenBank Accession No. CAC42515),
rat EGLN1 (GenBank Accession No. P59722), etc. Alternatively,
another HIF PH may be used in the assay. Such HIF PH enzymes
include, but are not limited to HIF PH1, also referred to as PHD1,
e.g., human EGLN2 isoform 1 (GenBank Accession No. CAC42510;
Taylor, supra), human EGLN2 isoform 3 (GenBank Accession No.
NP_542770), mouse EGLN2 (GenBank Accession No. CAC42516), and rat
EGLN2 (GenBank Accession No. AA046039), etc.; and any HIF PH3, also
referred to as PDH3, e.g. human EGLN3 (GenBank Accession No.
CAC42511; Taylor, supra), mouse EGLN3 (GenBank Accession No.
CAC42517), and rat EGLN3 (SM-20) (GenBank Accession No. AAA19321).
In other embodiments of the present disclosure, EGLN may include
Caenorhabditis elegans EGL-9 (GenBank Accession No. AAD56365) and
Drosophila melanogaster CG1114 gene product (GenBank Accession No.
AAF52050).
Pharmaceutical Formulations
[0066] The compound
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid (Compound A) is a potent inhibitor of hypoxia inducible factor
(HIF) prolyl hydroxylase and has the following formula:
##STR00001##
[0067] As described in the examples herein, it has recently been
discovered that Compound A undergoes photodecomposition after light
exposure to convert to a photodegradation product. The present
invention provides compositions (formulations) and methods that
prevent or reduce the amount of photodegradation of Compound A and
limit the amount of photodegradation product.
[0068] The pharmaceutical formulations described herein protect
Compound A from photodegradation. Accordingly, in one embodiment
the invention provides a pharmaceutical formulation comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, a pharmaceutically acceptable excipient, and an effective
amount of a photostabilizing agent. In a further embodiment, the
invention provides a pharmaceutical formulation comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, a pharmaceutically acceptable excipient, and an effective
amount of a photostabilizing agent, wherein the pharmaceutical
formulation comprises less than about 0.2% w/w (based on the amount
of API,
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid) photodegradation product of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
[0069] In one embodiment, the pharmaceutical formulation comprises
less than about 0.2% w/w (equivalent to 2000 ppm, based on the
amount of API) photodegradation product of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid after exposure of the formulation to light under ICH
conditions. The amount of photodegradation product can be readily
determined by one of ordinary skill in the art based on the
disclosure herein using routine analytical methods. If multiple
determinations of the amount of photode gradation product are made,
the mean value of the amount of photode gradation product from
multiple determinations is no more than about 0.2% w/w. The
condition of the light exposure (the kind of light source, the
power of the light source and the duration of light exposure) is
the ICH condition defined herein. The amount of photodegradation
product that is produced is readily determined by the methods
described herein, particularly by HPLC method. One skilled in the
formulations art can readily determine the effective amount of
photostabilizing agent sufficient to limit the amount of the
photodegradation product, based on the guidance and examples
provided herein.
[0070] In one embodiment, the photostabilizing agent is selected to
prevent or reduce photodegradation of Compound A. In one
embodiment, the photostabilizing agent prevents or reduces
photodegradation through effectively blocking light. In one
embodiment, the photostabilizing agent prevents or reduces
photodegradation through effectively blocking light in the
wavelength range of about 100 to about 800 nm, about 150 to about
700 nm, about 200 to about 550 nm, or about 360 to about 440 nm. In
one embodiment, the present invention provides a pharmaceutical
formulation comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, a pharmaceutically acceptable excipient, and an effective
amount of a photostabilizing agent, wherein the photostabilizing
agent comprises titanium dioxide and at least one additional dye.
In one embodiment, the dye blocks light at a wavelength range of
about 100 to about 800 nm, about 150 to about 700 nm, about 200 to
about 550 nm, or about 360 to about 440 nm.
[0071] In some embodiments, the photostabilizing agent comprises a
soluble dye, a dye lake, a pigment or a combination thereof. In one
embodiment, the photostabilizing agent comprises titanium dioxide
and at least one additional dye. In one embodiment, the dye is
selected from the group consisting of a black dye, a blue dye, a
green dye, a red dye, an orange dye, a purple dye, a violet dye, a
yellow dye, and combinations thereof. In another embodiment, the
dye is selected from the group consisting of a black dye, a blue
dye, a green dye, a red dye, an orange dye, a yellow dye, and
combinations thereof. In yet another embodiment, the dye is
selected from the group consisting of a red dye, an orange dye, a
yellow dye, and combinations thereof.
[0072] In another embodiment, the additional dye is selected from
the group consisting of Caramel, iron oxide black, iron oxide red,
iron oxide yellow, Allura Red AC, Allura Red AC aluminum lake,
Carmine, Erythrosine, beta-carotene or mixtures of carotenes,
Curcumin, Sunset Yellow FCF, Sunset Yellow FCF aluminum lake,
Tartrazine, chlorophylls and chlorophyllins or Cu complexes
thereof, Fast Green FCF, Brilliant Blue FCF, Indigotine, Indigotine
aluminum lake, and combinations thereof.
[0073] In one embodiment, the additional dye is selected from the
group consisting of iron oxide black, iron oxide red, iron oxide
yellow, Allura Red AC, Allura Red AC aluminum lake, Carmine,
Erythrosine, beta-carotene or mixtures of carotenes, Sunset Yellow
FCF, Sunset Yellow FCF aluminum lake, chlorophylls and
chlorophyllins or Cu complexes thereof, Fast Green FCF, Indigotine,
Indigotine aluminum lake, and combinations thereof.
[0074] In one embodiment, the additional dye is selected from the
group consisting of iron oxide black, iron oxide red, iron oxide
yellow, Allura Red AC, Allura Red AC aluminum lake, Carmine,
beta-carotene or mixtures of carotenes, Sunset Yellow FCF, Sunset
Yellow FCF aluminum lake, Indigotine, Indigotine aluminum lake, and
combinations thereof.
[0075] In another embodiment, the additional dye is selected from
the group consisting of Allura Red AC, Allura Red AC aluminum lake,
iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow
FCF aluminum lake, Indigotine, Indigotine aluminum lake, and
combinations thereof.
[0076] In one embodiment, the photostabilizing agent comprises
titanium dioxide and Allura Red AC aluminum lake. In one
embodiment, the photostabilizing agent comprises iron oxide red and
titanium dioxide. In one embodiment, the photostabilizing agent
comprises Allura Red AC, iron oxide yellow, and titanium dioxide.
In one embodiment, the photostabilizing agent comprises iron oxide
red, Allura Red AC, iron oxide yellow, and titanium dioxide. In one
embodiment, the photostabilizing agent comprises iron oxide red,
iron oxide yellow, and titanium dioxide. In one embodiment, the
photostabilizing agent comprises iron oxide yellow and titanium
dioxide.
[0077] In some embodiments, the photostabilizing agent comprises
titanium dioxide. In some embodiment, the photostabilizing agent
comprises a dye selected from the group consisting of a black dye,
a blue dye, a green dye, a red dye, an orange dye, a purple dye, a
violet dye, a yellow dye, and combinations thereof. In another
embodiment, the photostabilizing agent comprises a dye selected
from the group consisting of a black dye, a blue dye, a green dye,
a red dye, an orange dye, a yellow dye, and combinations thereof.
In yet another embodiment, the photostabilizing agent comprises a
dye selected from the group consisting of a red dye, an orange dye,
a yellow dye, and combinations thereof.
[0078] In one embodiment, the photostabilizing agent comprises a
dye selected from the group consisting of Caramel, iron oxide
black, iron oxide red, iron oxide yellow, Allura Red AC, Allura Red
AC aluminum lake, Carmine, Erythrosine, beta-carotene or mixtures
of carotenes, Curcumin, Sunset Yellow FCF, Sunset Yellow FCF
aluminum lake, Tartrazine, chlorophylls and chlorophyllins or Cu
complexes thereof, Fast Green FCF, Brilliant Blue FCF, Indigotine,
Indigotine aluminum lake, and combinations thereof.
[0079] In one embodiment, the pharmaceutical formulation comprises
from about 1 mg to about 400 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In another embodiment, the pharmaceutical formulation
comprises from about 20 mg to about 200 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In another embodiment, the pharmaceutical formulation
comprises about 1 mg, about 5 mg, about 10 mg, about 15 mg, about
20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about
125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg,
about 300 mg, about 350 mg, or about 400 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In yet another embodiment, the pharmaceutical formulation
comprises about 20 mg, about 50 mg, or about 100 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In yet another embodiment, the pharmaceutical formulation
comprises about 20 mg, or about 50 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
[0080] In one embodiment, the pharmaceutical formulation comprises
from about 1% to about 90% w/w
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In another embodiment, the pharmaceutical formulation
comprises from about 0.1% to about 50% w/w photostabilizing agent.
In another embodiment, the pharmaceutical formulation comprises
from about 1% to about 7% w/w photostabilizing agent. In each
embodiment, the pharmaceutical formulation comprises a
pharmaceutically acceptable excipient. The pharmaceutically
acceptable excipient may include fillers such as sugars, including
lactose, lactose monohydrate, sucrose, mannitol, or sorbitol;
cellulose preparations such as, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth, methyl
cellulose, hydroxypropylmethyl-cellulose, carboxymethylcellulose
sodium, microcrystalline cellulose and/or polyvinylpyrrolidone (PVP
or povidone), disintegrating agents, such as the cross-linked
polyvinyl pyrrolidone, agar, croscarmellose sodium or alginic acid
or a salt thereof such as sodium alginate, and wetting agents such
as sodium dodecyl sulfate or lubricants such as magnesium stearate.
In one embodiment, the pharmaceutical formulation comprises one or
more pharmaceutically acceptable excipients selected from lactose
monohydrate, microcrystalline cellulose, povidone, croscarmellose
sodium, or magnesium stearate.
[0081] In one embodiment, a solid dosage form comprises the
pharmaceutical formulation and the solid dosage form is selected
from a capsule, tablet, bead, granule, pellet, lozenge, pill, or
gum. In another embodiment, the solid dosage form is a tablet. In
another embodiment, the solid dosage form is a capsule.
Tablet
[0082] The present disclosure provides a tablet comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, a pharmaceutically acceptable excipient and an effective
amount of a photostabilizing agent. In one embodiment, the tablet
comprises a tablet core and a coating.
[0083] In some embodiments, the photostabilizing agent is blended
into the tablet or the tablet core. A tablet or a tablet core is
prepared by mixing API with one or more excipients such as fillers
(diluents), binders, disintegrating agents, lubricants, and
glidants; and then by compressing the mixture. In the embodiments
in which the photostabilizing agent is blended into the tablet or
the tablet core, the photostabilizing agent is mixed (blended) with
API and excipient, and then the mixture is compressed to form a
tablet or a tablet core. Methods of preparing such compressed
tablets and tablet cores are well known in the pharmaceutical
arts.
[0084] In one embodiment, the tablet comprises a tablet core and a
coating, wherein the tablet core comprises
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid and the pharmaceutically acceptable excipient, and the coating
comprises the photostabilizing agent.
[0085] Based on the description and examples provided herein and
routine practices in the formulations art, one of skill in the art
will be able to determine the appropriate amount of coating
containing the photostabilizing agent in terms of density and
thickness to provide the photostabilization. In one embodiment, the
coating is present in the tablet in an amount that is about 3% to
about 8% w/w based on the weight of the tablet core. For example,
from about 7% to about 8% w/w of coating can be applied to a 80 mg
tablet core; from about 5% to about 6% w/w of coating can be
applied to a 200 mg tablet core; or from about 4% to about 5% w/w
of coating can be applied to a 400 mg tablet core. The amount of
the photostabilizing agent in these coatings may vary and is
described herein (for example, see Example 2). Non-limiting
examples of coating include polyvinylalcohol-based,
hydroxyethylcellulose, hydroxypropylmethylcellulose,
carboxymethylcellulose sodium, polyethylene glycol 4000 and
cellulose acetate phthalate coatings. In one embodiment, the
coating is a polyvinylalcohol-based coating.
[0086] In one embodiment, the photostabilizing agent in the tablet
comprises titanium dioxide and at least one additional dye selected
from the group consisting of Allura Red AC, Allura Red AC aluminum
lake, iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset
Yellow FCF aluminum lake, Indigotine, Indigotine aluminum lake, and
combinations thereof. In another embodiment, the photostabilizing
agent comprises titanium dioxide and Allura Red AC aluminum
lake.
[0087] One of skill in the art will be able to determine the
effective amount of photostabilizing agent needed to prevent or
reduce the photodegradation. The amount of photostabilizing agent
in the coating can be described as % w/w, percent weight of the
photostabilizing agent based on the coating weight. In one
embodiment, the coating comprises from about 0.1% to about 50% w/w
photostabilizing agent (based on coating weight). In another
embodiment, the coating comprises from about 0.5% to about 40% w/w
photostabilizing agent (based on coating weight). In another
embodiment, the coating comprises from about 2% to about 35%
photostabilizing agent (based on coating weight).
[0088] The amount of photostabilizing agent in the coating can also
be described as the weight of the photostabilizing agent applied
per surface area unit of the tablet core (mg/cm.sup.2). To
determine the amount of photostabilizing agent needed to prevent or
reduce photodegradation, the tablet core can be coated with various
amounts of coatings and each coating may contain different dyes at
different quantities. Photodegradation can be monitored by the
appearance of photodegradation product, if any, upon light exposure
(either under ICH condition or sunlight). Example 2 describes
various coatings with different dye compositions and their
photostabilization results. In the coating, when dye is present in
the form of its aluminum lake, the amount of dye refers to the
total amount of pure dye in its aluminum lake, not including other
components of the aluminum lake.
[0089] In one embodiment, the photostabilizing agent in the coating
comprises at least about 0.1 mg/cm.sup.2 titanium dioxide and at
least one additional dye selected from the group consisting of:
[0090] at least about 0.1 mg/cm.sup.2 Allura Red AC;
[0091] at least about 0.1 mg/cm.sup.2 Allura Red AC in aluminum
lake;
[0092] at least about 0.004 mg/cm.sup.2 iron oxide red;
[0093] at least about 0.009 mg/cm.sup.2 iron oxide yellow;
[0094] at least about 0.01 mg/cm.sup.2 Sunset Yellow FCF; and
[0095] at least about 0.01 mg/cm.sup.2 Sunset Yellow FCF in
aluminum lake;
[0096] wherein the amount of photostabilizing agent is based on the
surface area of the tablet core.
[0097] In another embodiment, the photostabilizing agent in the
coating comprises from about 0.1 to about 2 mg/cm.sup.2 titanium
dioxide and at least one additional dye selected from the group
consisting of;
[0098] from about 0.1 to about 0.4 mg/cm.sup.2 Allura Red AC;
[0099] from about 0.1 to about 0.4 mg/cm.sup.2 Allura Red AC in
aluminum lake;
[0100] from about 0.004 to about 0.4 mg/cm.sup.2 iron oxide
red;
[0101] from about 0.009 to about 0.2 mg/cm.sup.2 iron oxide
yellow;
[0102] from about 0.01 to 0.03 mg/cm.sup.2 Sunset Yellow FCF, and
from about 0.01 to 0.03 mg/cm.sup.2 Sunset Yellow FCF in aluminum
lake;
[0103] wherein the amount of photostabilizing agent is based on the
surface area of the tablet core.
[0104] In yet another embodiment, the photostabilizing agent in the
coating comprises, based on surface area of the tablet core, from
about 0.1 to about 2 mg/cm.sup.2 or from about 0.1 to about 0.4
mg/cm.sup.2 titanium dioxide, and from about 0.1 to about 0.4
mg/cm.sup.2 Allura Red AC or Allura Red AC in aluminum lake.
[0105] Further examples of various suitable amounts of
photostabilizing agents applied to tablet cores are given in
Example 2.
[0106] In some embodiments, the tablet core comprises from about 1%
to about 90% w/w, from about 5% to about 80% w/w, from about 5% to
about 40% w/w, from about 11% to about 30% w/w, 20% to about 30%
w/w or from about 22% to about 28% w/w
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, and a pharmaceutically acceptable excipient.
[0107] In some embodiments, the tablet core comprises about 1 mg to
about 400 mg, or about 20 mg to about 200 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, and a pharmaceutically acceptable excipient. In other
embodiments, the tablet core comprises about 1 mg, about 5 mg,
about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg,
about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175
mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or
about 400 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, and a pharmaceutically acceptable excipient. In other
embodiments, the tablet core comprises about 20 mg, about 50 mg, or
about 100 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, and a pharmaceutically acceptable excipient.
[0108] Suitable excipients are, for example, fillers such as
sugars, including lactose, lactose monohydrate, sucrose, mannitol,
or sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose,
carboxymethylcellulose sodium, microcrystalline cellulose and/or
polyvinylpyrrolidone (PVP or povidone). If desired, disintegrating
agents may be added, such as the cross-linked polyvinyl
pyrrolidone, agar, croscarmellose sodium or alginic acid or a salt
thereof such as sodium alginate. Also, wetting agents such as
sodium dodecyl sulfate or lubricants such as magnesium stearate may
be included.
[0109] In one embodiment, the pharmaceutically acceptable excipient
comprises lactose monohydrate, microcrystalline cellulose,
povidone, croscarmellose sodium, and magnesium stearate.
[0110] The present disclosure provides a tablet comprising a tablet
core and a coating, wherein the tablet core comprises
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid and a pharmaceutically acceptable excipient, and the coating
comprises an effective amount of a photostabilizing agent, wherein
the coating is present in an amount from about 3% to about 8% w/w
(based on the weight of the tablet core).
[0111] In one embodiment, the tablet core comprises from about 22%
to about 28% w/w
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid (based on the weight of the tablet core) and a
pharmaceutically acceptable excipient. In one embodiment, the
pharmaceutically acceptable excipient comprises lactose
monohydrate, microcrystalline cellulose, povidone, croscarmellose
sodium, and magnesium stearate. In another embodiment, the tablet
core comprises from about 20 mg to about 200 mg
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In another embodiment, the tablet core comprises about 20 mg,
about 50 mg or about 100 mg
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid.
[0112] In one embodiment, the photostabilizing agent comprises
titanium dioxide and at least one additional dye selected from the
group consisting of Allura Red AC, Allura Red AC aluminum lake,
iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow
FCF aluminum lake, Indigotine, Indigotine aluminum lake, and
combinations thereof. In another embodiment, the photostabilizing
agent comprises titanium dioxide and Allura Red AC aluminum lake.
In yet another embodiment, the coating comprises from about 0.1 to
about 0.4 mg/cm.sup.2 titanium dioxide and from about 0.1 to about
0.4 mg/cm.sup.2 Allura Red AC in aluminum lake wherein the amount
of titanium dioxide and Allura Red AC in aluminum lake is based on
surface area of the tablet core.
[0113] The present disclosure provides a tablet comprising a tablet
core and a coating, wherein the tablet core comprises
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid and a pharmaceutically acceptable excipient, and the coating
comprises an effective amount of a photostabilizing agent, wherein
the coating is present in an amount from about 3% to about 8% w/w
(based on the weight of the tablet core), wherein the tablet core
comprises about 20 mg, about 50 mg or about 100 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
photostabilizing agent comprises 0.1 to about 0.4 mg/cm.sup.2
titanium dioxide and from about 0.1 to about 0.4 mg/cm.sup.2 Allura
Red AC in aluminum lake wherein the amount of titanium dioxide and
Allura Red AC in aluminum lake is based on surface area of the
tablet core.
Capsule
[0114] The present disclosure provides a capsule comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, a pharmaceutically acceptable excipient and an effective
amount of a photostabilizing agent. In one embodiment, the capsule
comprises a capsule fill and a capsule shell, wherein the capsule
fill comprises
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid and the pharmaceutically acceptable excipient, and the capsule
shell comprises the photostabilizing agent.
[0115] In some embodiments, the capsule fill comprises the
photostabilizing agent,
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid, and the pharmaceutically acceptable excipient. In these
embodiments, the capsule fill is prepared by mixing (blending) the
photostabilizing agent with API and excipients.
[0116] In some embodiments, the photostabilizing agent in the
capsule comprises titanium dioxide and at least one additional dye
selected from the group consisting of Allura Red AC, iron oxide
red, iron oxide yellow, and combinations thereof. In another
embodiment, the photostabilizing agent comprises iron oxide red and
titanium dioxide. In another embodiment, the photostabilizing agent
comprises iron oxide red, Allura Red AC, iron oxide yellow, and
titanium dioxide. In yet another embodiment, the photostabilizing
agent comprises iron oxide red, iron oxide yellow, and titanium
dioxide. In still yet another embodiment, the photostabilizing
agent comprises Allura Red AC, iron oxide yellow, and titanium
dioxide. In still yet another embodiment, the photostabilizing
agent comprises iron oxide yellow and titanium dioxide.
[0117] Based on the disclosure herein and routine experimentation,
one of skill in the art will readily be able to determine the
effective amount of photostabilizing agent needed to prevent or
reduce the photodegradation of Compound A in the capsule. The
amount of photostabilizing agent in the capsule shell can be
described as % w/w, percent weight of the photostabilizing agent
based on the capsule shell weight. To determine the amount of
photostabilizing agent needed to prevent or reduce the
photodegradation of Compound A, capsules with capsule shells
containing different dyes in different quantities can be tested for
photostabilization. As an alternative, the capsule fills containing
Compound A can be covered with gelatin films containing different
dyes in different quantities, and the photodegradation of Compound
A, if any, can be monitored following light exposure (either under
ICH condition or sunlight). Example 3 describes several gelatin
films with various dye compositions and their photostabilization
results.
[0118] In one embodiment, the capsule shell comprises from about 1%
w/w to about 7% w/w, from about 1.8% w/w to about 6% w/w, from
about 2% w/w to about 4% w/w, or from about 2% w/w to about 3.5%
w/w photostabilizing agent (based on weight of capsule shell). In
another embodiment, the capsule shell comprises from about 1.8% w/w
to about 6% w/w photostabilizing agent (based on weight of capsule
shell). In another embodiment, the capsule shell comprises from
about 2% w/w to about 3.5% w/w photostabilizing agent (based on
weight of capsule shell).
[0119] In one embodiment, the capsule shell is a gelatin shell. In
another embodiment, the capsule shell is a
hydroxypropylmethylcellulose (HPMC) shell.
[0120] In one embodiment, the capsule shell comprises about 2% w/w
iron oxide red and about 0.9% w/w titanium dioxide (based on weight
of capsule shell); or about 0.3% w/w Allura Red AC, about 1% w/w
iron oxide yellow, and about 1% w/w titanium dioxide (based on
weight of capsule shell); or about 0.7% w/w iron oxide red, about
0.3% w/w Allura Red AC, about 1% w/w iron oxide yellow, and about
1% w/w titanium dioxide (based on weight of capsule shell); or
about 1% w/w iron oxide red, about 1% w/w iron oxide yellow, and
about 1% w/w titanium dioxide (based on weight of capsule shell);
or about 1% w/w Allura Red AC, about 1% w/w iron oxide yellow, and
about 1% w/w titanium dioxide (based on weight of capsule shell);
or about 2% w/w iron oxide red and about 1% w/w titanium dioxide
(based on weight of capsule shell); or about 2% w/w iron oxide
yellow and about 1% w/w titanium dioxide (based on weight of
capsule shell).
[0121] In some embodiments, the capsule fill comprises
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid in an amount from about 1% to about 90% w/w, from about 5% to
about 80% w/w, from about 5% to about 40% w/w, from about 8% to
about 30% w/w, 10% to about 30% w/w or from about 12% to about 15%
w/w (based on the weight of the capsule fill); and a
pharmaceutically acceptable excipient.
[0122] In some embodiments, the capsule fill comprises about 1 mg
to about 400 mg, about 5 mg to about 250 mg, about 20 mg to about
200 mg, about 20 mg to about 100 mg or about 20 mg to about 50 mg
of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid; and a pharmaceutically acceptable excipient. In other
embodiments, the capsule fill comprises about 1 mg, about 5 mg,
about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg,
about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175
mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or
about 400 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid; and a pharmaceutically acceptable excipient. In other
embodiments, the capsule fill comprises about 20 mg, or about 50 mg
of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid; and a pharmaceutically acceptable excipient.
[0123] Suitable excipients are, for example, fillers such as
sugars, including lactose, lactose monohydrate, sucrose, mannitol,
or sorbitol; cellulose preparations such as, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose,
carboxymethylcellulose sodium, microcrystalline cellulose and/or
polyvinylpyrrolidone (PVP or povidone). If desired, disintegrating
agents may be added, such as the cross-linked polyvinyl
pyrrolidone, agar, croscarmellose sodium or alginic acid or a salt
thereof such as sodium alginate. Also, wetting agents such as
sodium dodecyl sulfate or lubricants such as magnesium stearate may
be included.
[0124] In one embodiment, the pharmaceutically acceptable excipient
in the capsule comprises lactose monohydrate, microcrystalline
cellulose, povidone, croscarmellose sodium, and magnesium
stearate.
[0125] The present disclosure provides a capsule comprising a
capsule fill and a capsule shell, wherein the capsule fill
comprises from about 12% to about 15% w/w
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid (based on the weight of the capsule fill) and a
pharmaceutically acceptable excipient, and wherein the capsule
shell comprises an effective amount of a photostabilizing agent. In
one embodiment, the pharmaceutically acceptable excipient comprises
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate. In another
embodiment, the capsule fill comprises about 20 mg or about 50 mg
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid. In yet another embodiment, the capsule shell comprises from
about 2% w/w to about 3.5% w/w photostabilizing agent (based on the
weight of the capsule shell).
[0126] In one embodiment, the capsule fill comprises about 20 mg or
about 50 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-a-
cetic acid, and pharmaceutically acceptable excipients comprising
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
capsule shell is a gelatin shell comprising about 2% w/w iron oxide
red and about 0.9% w/w titanium dioxide (based on the weight of the
capsule shell).
[0127] In one embodiment, the capsule fill comprises about 20 mg or
about 50 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-a-
cetic acid, and pharmaceutically acceptable excipients comprising
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
capsule shell is a gelatin shell comprising about 0.3% w/w Allura
Red AC, about 1% w/w iron oxide yellow, and about 1% w/w titanium
dioxide (based on the weight of the capsule shell).
[0128] In one embodiment, the capsule fill comprises about 20 mg or
about 50 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-a-
cetic acid, and pharmaceutically acceptable excipients comprising
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
capsule shell is a gelatin shell comprising about 0.7% w/w iron
oxide red, about 0.3% w/w Allura Red AC, about 1% w/w iron oxide
yellow, and about 1% w/w titanium dioxide (based on the weight of
the capsule shell).
[0129] In one embodiment, the capsule fill comprises about 20 mg or
about 50 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-a-
cetic acid, and pharmaceutically acceptable excipients comprising
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
capsule shell is a gelatin shell comprising about 1% w/w iron oxide
red, about 1% w/w iron oxide yellow, and about 1% w/w titanium
dioxide (based on the weight of the capsule shell).
[0130] In one embodiment, the capsule fill comprises about 20 mg or
about 50 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-a-
cetic acid, and pharmaceutically acceptable excipients comprising
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
capsule shell is a gelatin shell comprising about 1% w/w Allura Red
AC, about 1% w/w iron oxide yellow, and about 1% w/w titanium
dioxide (based on the weight of the capsule shell).
[0131] In one embodiment, the capsule fill comprises about 20 mg or
about 50 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-a-
cetic acid, and pharmaceutically acceptable excipients comprising
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
capsule shell is a gelatin shell comprising about 2% w/w iron oxide
red, and about 1% w/w titanium dioxide (based on the weight of the
capsule shell).
[0132] In one embodiment, the capsule fill comprises about 20 mg or
about 50 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-a-
cetic acid, and pharmaceutically acceptable excipients comprising
lactose monohydrate, microcrystalline cellulose, povidone,
croscarmellose sodium, and magnesium stearate; and wherein the
capsule shell is a gelatin shell comprising about 2% w/w iron oxide
yellow, and about 1% w/w titanium dioxide (based on the weight of
the capsule shell).
Routes of Administration
[0133] Suitable routes of administration may, for example, include
oral, rectal, transmucosal, nasal, or intestinal administration and
parenteral delivery, including intramuscular, subcutaneous,
intramedullary injections, as well as intrathecal, direct
intraventricular, intravenous, intraperitoneal, intranasal, or
intraocular injections. The pharmaceutical formulation may be
administered in a local rather than a systemic manner. For example,
pharmaceutical formulation can be delivered via injection or in a
targeted drug delivery system, such as a depot or sustained release
formulation. In one embodiment, the route of administration is
oral. When the pharmaceutical formulation is administered orally,
it may be administered as a tablet or a capsule.
[0134] The pharmaceutical formulations of the present disclosure
may be manufactured by any of the methods well-known in the art,
such as by conventional mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping,
or lyophilizing processes. As noted above, the compositions can
include one or more pharmaceutically acceptable excipients that
facilitate processing of active molecules into preparations for
pharmaceutical use.
[0135] Proper formulation is dependent upon the route of
administration chosen. For injection, for example, the composition
may be formulated in aqueous solutions, preferably in
physiologically compatible buffers such as Hanks' solution,
Ringer's solution, or physiological saline buffer. For transmucosal
or nasal administration, penetrants appropriate to the barrier to
be permeated are used in the formulation. Such penetrants are
generally known in the art. In one embodiment of the present
disclosure, the pharmaceutical formulations are intended for oral
administration. For oral administration, it can be formulated
readily by combining Compound A with pharmaceutically acceptable
excipients well known in the art. Such excipients enable Compound A
to be formulated as tablets, pills, dragees, capsules, liquids,
gels, syrups, slurries, suspensions and the like, for oral
ingestion by a subject. The pharmaceutical formulation may also be
formulated into rectal compositions such as suppositories or
retention enemas, e.g., containing conventional suppository bases
such as cocoa butter or other glycerides.
[0136] Pharmaceutical preparations for oral use can be obtained
using solid excipients, optionally grinding a resulting mixture,
and processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain tablets or tablet cores.
Suitable excipients are well known in the art and are described
elsewhere herein.
[0137] Pharmaceutical preparations for oral administration include
push-fit capsules made of gelatin, HPMC, and other suitable
materials, as well as soft, sealed capsules made of gelatin and a
plasticizer, such as glycerol or sorbitol. The push-fit capsules
can contain the active ingredients in admixture with filler such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active ingredients may be dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. In addition, stabilizers may be added.
[0138] The pharmaceutical formulations may also be formulated as a
depot preparation. Such long acting formulations may be
administered by implantation (for example, subcutaneously or
intramuscularly) or by intramuscular injection. Thus, for example,
the pharmaceutical formulations may be formulated with suitable
polymeric or hydrophobic materials (for example as an emulsion in
an acceptable oil) or ion exchange resins, or as sparingly soluble
derivatives, for example, as a sparingly soluble salt.
[0139] For any composition used in the various treatments embodied
herein, an effective dose (or therapeutically effective dose) can
be estimated initially using a variety of techniques well known in
the art. For example, in a cell culture assay, a dose can be
formulated in animal models to achieve a circulating concentration
range that includes the IC.sub.50 as determined in cell culture.
Dosage ranges appropriate for human subjects can be determined, for
example, using data obtained from cell culture assays and non-human
animal studies. In one embodiment, the dosage may be from 0.05
mg/kg to about 700 mg/kg. Typically, the dosage may be from about
0.05 mg/kg to about 500 mg/kg; from about 0.1 mg/kg to about 250
mg/kg; from about 0.2 mg/kg to about 100 mg/kg; from about 0.3
mg/kg to about 10 mg/kg; from about 0.5 mg/kg to about 5 mg/kg; or
from about 1 mg/kg to about 2 mg/kg. For example, the dosage may be
about 0.5 mg/kg; about 0.7 mg/kg; 1.0 mg/kg; about 1.2 mg/kg; about
1.5 mg/kg; about 2.0 mg/kg; about 2.5 mg/kg; about 3.0 mg/kg; about
3.5 mg/kg; about 4.0 mg/kg; about 4.5 mg/kg; or about 5.0 mg/kg.
The dosages may be administered at various intervals, for example,
every day, every other day, 1, 2, or 3 times a week, etc.
Typically, the dosages is administered 2 or 3 times a week.
[0140] A therapeutically effective dose of a compound refers to
that amount of the compound that results in amelioration of
symptoms or a prolongation of survival in a subject. Toxicity and
therapeutic efficacy of such molecules can be determined by
standard pharmaceutical procedures in cell cultures or experimental
animals, e.g., by determining the LD.sub.50 (the dose lethal to 50%
of the population) and the ED.sub.50 (the dose therapeutically
effective in 50% of the population). The dose ratio of toxic to
therapeutic effects is the therapeutic index, which can be
expressed as the ratio LD.sub.50/ED.sub.50. Compounds that exhibit
high therapeutic indices are preferred.
[0141] Dosages preferably fall within a range of circulating
concentrations that includes the ED.sub.50 with little or no
toxicity. Dosages may vary within this range depending upon the
dosage form employed and the route of administration utilized. The
exact formulation, route of administration, and dosage should be
chosen, according to methods known in the art, in view of the
specifics of a subject's condition.
[0142] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active moiety that are sufficient to
modulate a desired parameter, e.g., endogenous erythropoietin
plasma levels, i.e. minimal effective concentration (MEC). The MEC
will vary for each compound but can be estimated from, for example,
in vitro data. In cases of local administration or selective
uptake, the effective local concentration of the drug may not be
related to plasma concentration. Alternatively, modulation of a
desired parameter, e.g., stimulation of endogenous erythropoietin,
may be achieved by 1) administering a loading dose followed by a
maintenance dose, 2) administering an induction dose to rapidly
achieve the desired parameter, e.g., erythropoietin levels, within
a target range, followed by a lower maintenance dose to maintain,
e.g., hematocrit, within a desired target range, or 3) repeated
intermittent dosing.
[0143] The amount of compound or composition administered will, of
course, be dependent on a variety of factors, including the sex,
age, and weight of the subject being treated, the severity of the
affliction, the manner of administration, and the judgment of the
prescribing physician.
[0144] The present compositions may, if desired, be presented in a
pack or dispenser device containing one or more unit dosage forms
containing the active ingredient. Such a pack or device may, for
example, comprise metal or plastic foil, such as a blister pack.
The pack or dispenser device may be accompanied by instructions for
administration. Pharmaceutical formulations of the disclosure
formulated in a compatible pharmaceutical excipient may also be
prepared, placed in an appropriate container, and labeled for
treatment of an indicated condition. Suitable conditions indicated
on the label may include treatment of conditions, disorders, or
diseases in which anemia is a major indication.
Methods
[0145] The present disclosure provides a method of inhibiting
(preventing and/or reducing) the photodegradation of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid (Compound A). In one embodiment, the method comprises
formulating
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid with an effective amount of a photostabilizing agent. An
effective amount of photostabilizing agent is the amount sufficient
to limit the amount of photodegradation product of Compound A that
is produced to a level that is less than about 0.2% w/w Compound A
(or 2000 ppm), under ICH conditions. In one embodiment, the
photostabilizing agent comprises titanium dioxide. In one
embodiment, the photostabilizing agent comprises a dye. In some
embodiments, the method comprises formulating
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid with titanium dioxide and at least one additional dye. In a
further embodiment, the photostabilizing agent blocks light at a
wavelength range of between about 220 and about 550 nm. In other
embodiments, the dye is selected from the group consisting of a
black dye, a blue dye, a green dye, a red dye, an orange dye, a
yellow dye, and combinations thereof. In another embodiment, the
dye is selected from the group consisting of a red dye, an orange
dye, a yellow dye, and combinations thereof. The present invention
further provides a method of inhibiting (preventing and/or
reducing) the photodegradation of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid (Compound A), the method comprising formulating
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid with an effective amount of a photostabilizing agent, and a
pharmaceutically acceptable excipient. Various formulations
comprising photostabilizing agents have been described herein.
[0146] Compound A can be formulated with the photostabilizing agent
in any conventional manner, for example, by mixing or blending
Compound A and photostabilizing agent together into a homogeneous
dry powder, compressing into solid tablet forms, filling into
capsules, etc. Alternatively, Compound A can be formulated with the
photostabilizing agent by coating a tablet core comprising Compound
A with a coating comprising the photostabilizing agent, or by
enclosing a capsule fill comprising Compound A within a capsule
shell comprising the photostabilizing agent.
[0147] In other embodiments, the method of inhibiting the
photodegradation of Compound A can be achieved with
photostabilizing packaging, either as an alternative, or as an
addition to the photostabilizing formulation. Examples of
photostabilizing packaging for tablets or capsules include, but are
not limited to, opaque containers or wrappings such as, a brown
bottle, a black-lined bottle, an amber vial, an opaque blister
pack, a blister pack made from a blister film containing a
photostabilizing agent, and a foil-lined packaging.
[0148] One aspect of the disclosure provides for use of the
pharmaceutical formulations for the manufacture of a medicament for
use in treating various conditions or disorders as described
herein. It also provides methods of using the pharmaceutical
formulation or composition or medicament thereof, to treat,
pretreat, or delay progression or onset of various conditions or
disorders as described herein.
[0149] The medicaments or compositions can be used to modulate the
stability and/or activity of HIF, and thereby activate
HIF-regulated gene expression. In one aspect, the medicaments or
compositions can be used to inhibit or reduce the activity of a HIF
hydroxylase enzyme, particularly a HIF prolyl hydroxylase enzyme,
for example, EGLN1, EGLN2, and EGLN3 (also known as PHD2, PHD1 and
PHD3, respectively), described by Taylor (2001, Gene 275:125-132),
and characterized by Aravind and Koonin (2001, Genome Biol
2:RESEARCH0007), Epstein et al. (2001, Cell 107:43-54), and Bruick
and McKnight (2001, Science 294:1337-1340).
[0150] The pharmaceutical formulations described herein can be used
in methods to treat, pretreat, or delay progression or onset of
conditions associated with HIF including, but not limited to,
anemic, ischemic, and hypoxic conditions. In various embodiments,
the pharmaceutical formulation is administered immediately
following a condition producing acute ischemia, e.g., myocardial
infarction, pulmonary embolism, intestinal infarction, ischemic
stroke, and renal ischemic-reperfusion injury. In another
embodiment, pharmaceutical formulation is administered to a patient
diagnosed with a condition associated with the development of
chronic ischemia, e.g., cardiac cirrhosis, macular degeneration,
pulmonary embolism, acute respiratory failure, neonatal respiratory
distress syndrome, and congestive heart failure. In yet another
embodiment, pharmaceutical formulation is administered immediately
after a trauma or injury. In other embodiments, pharmaceutical
formulation can be administered to a subject based on predisposing
conditions, e.g., hypertension, diabetes, occlusive arterial
disease, chronic venous insufficiency, Raynaud's disease, chronic
skin ulcers, cirrhosis, congestive heart failure, and systemic
sclerosis. In still other embodiments, pharmaceutical formulation
may be administered to pretreat a subject to decrease or prevent
the development of tissue damage associated with ischemia or
hypoxia. In other embodiments, the pharmaceutical formulations and
compositions can be used in a method to treat or delay progression
of inflammatory bowel disease, including various forms of colitis
(e.g., ulcerative colitis) and Crohn's disease.
[0151] The pharmaceutical formulations and compositions can be used
in a method to treat anemia, to increase blood hemoglobin levels,
and/or to increase hematocrit, in a subject in need thereof. In one
aspect, the pharmaceutical formulations and compositions can be
used in a method to treat anemia, to increase blood hemoglobin
levels, and/or to increase hematocrit, in a subject with chronic
kidney disease or end stage renal disorder. In one aspect, the
pharmaceutical formulations and compositions can be used in a
method to treat anemia, to increase blood hemoglobin levels, and/or
to increase hematocrit, in a subject having anemia of chronic
disease.
[0152] The pharmaceutical formulations and compositions can also be
used in a method for regulating glucose metabolism and achieving
glucose homeostasis. Methods for decreasing blood glucose levels,
reducing insulin resistance, decreasing glycated hemoglobin levels,
decreasing blood triglyceride levels, and improving glycemic
control in a subject are also accomplished by administering the
formulations or compositions described herein. Methods for treating
or preventing diabetes, hyperglycemia, and other conditions
associated with increased blood glucose levels are provided, as are
methods for treating or preventing conditions associated with
diabetes, e.g., conditions that are risk factors for or that
develop in parallel with or as a result of diabetes.
[0153] The pharmaceutical formulation can also be used to increase
endogenous erythropoietin (EPO). The pharmaceutical formulation can
be administered to prevent, pretreat, or treat EPO-associated
conditions, including, e.g., conditions associated with anemia and
neurological disorders. Conditions associated with anemia include
disorders such as acute or chronic kidney disease, diabetes,
cancer, ulcers, infection with virus, e.g., HIV, bacteria, or
parasites; inflammation, etc. Anemic conditions can further include
those associated with procedures or treatments including, e.g.,
radiation therapy, chemotherapy, dialysis, and surgery. Disorders
associated with anemia additionally include abnormal hemoglobin
and/or erythrocytes, such as found in disorders such as microcytic
anemia, hypochromic anemia, aplastic anemia, etc.
[0154] In one aspect, the pharmaceutical formulations and
compositions can be used in a method for inducing enhanced or
complete erythropoiesis in a subject.
[0155] The disclosure is also directed to use of a pharmaceutical
formulation to treat, pretreat, or delay onset of a condition
associated with a disorder selected from the group consisting of
anemic disorders; neurological disorders and/or injuries including
cases of stroke, trauma, epilepsy, and neurodegenerative disease;
cardiac ischemia including, but not limited to, myocardial
infarction and congestive heart failure; liver ischemia including,
but not limited to, cardiac cirrhosis; renal ischemia including,
but not limited to, acute kidney failure and chronic kidney
failure; peripheral vascular disorders, ulcers, burns, and chronic
wounds; pulmonary embolism; and ischemic-reperfusion injury. In one
aspect the formulations and compositions are useful in a method for
treating multiple sclerosis and/or increasing neurogenesis.
[0156] In a further aspect, the formulations and compositions can
be used in a method for reducing blood pressure or preventing an
increase in blood pressure and for treating or preventing
hypertension or prehypertension in any subject, including, but not
limited to, subjects having kidney disease.
[0157] In another embodiment, the present invention provides use
for the formulations and compositions in a method for improving
kidney function in a subject having or at risk for having impaired
kidney function, the method comprising administering to the subject
an agent that inhibits hypoxia inducible factor (HIF) hydroxylase
activity.
[0158] In another aspect, the formulations and compositions can be
used in a method for regulation of iron processing and
treatment/prevention of conditions associated with deficiencies in
iron and/or iron processing. In certain aspects, the invention
contemplates use of the formulations and compositions in methods
for increasing serum iron, increasing transferrin saturation,
increasing soluble transferrin receptor levels, and increasing
serum ferritin levels in a subject.
[0159] In another aspect, the formulations and compositions can be
used in methods for treatment of high cholesterol by reducing the
circulating level of total cholesterol and particularly by reducing
the circulating level of low density lipoprotein cholesterol and/or
very low density lipoprotein cholesterol, and/or increasing the
ratio of high density lipoprotein cholesterol/low density protein
cholesterol.
[0160] Methods of using HIF prolyl hydroxylase inhibitors, and in
particular, Compound A, to treat various conditions and disorders
have been described in numerous publications including, U.S. Patent
Application Publication Nos. 2003/0176317, 2003/0153503,
2004/0204356, 2004/0235082, 2005/0020487, 2007/0042937,
2007/0004627, 2006/0276477, 2007/0293575, 2012/0149712,
2007/0259960, 2007/0292433, 2011/0039878, 2011/0039885,
2010/0144737, 2011/0039879, and 2011/0263642; PCT Publication No.
WO2012/097329, WO2012/097331, and WO2013/070908; International
Patent Application No. PCT/US2013/029851.
[0161] The disclosure is also directed to a method of inhibiting
the activity of at least one hydroxylase enzyme which modifies the
alpha subunit of hypoxia inducible factor. The HIF hydroxylase
enzyme may be a prolyl hydroxylase including, but not limited to,
the group consisting of EGLN1, EGLN2, and EGLN3 (also known as
PHD2, PHD1 and PHD3, respectively), described by Taylor (2001, Gene
275:125-132), and characterized by Aravind and Koonin (2001, Genome
Biol 2:RESEARCH0007), Epstein et al. (2001, Cell 107:43-54), and
Bruick and McKnight (2001, Science 294:1337-1340). The method
comprises contacting the enzyme with Compound A. In some
embodiments, the HIF hydroxylase enzyme is an asparaginyl
hydroxylase or a prolyl hydroxylase. In other embodiments, the HIF
hydroxylase enzyme is a factor inhibiting HIF, human EGLN1, EGLN2,
or EGLN3.
[0162] While this disclosure has been described in conjunction with
specific embodiments and examples, it will be apparent to a person
of ordinary skill in the art, having regard to that skill and this
disclosure, that equivalents of the specifically disclosed
materials and methods will also be applicable to this disclosure;
and such equivalents are intended to be included within the
following claims.
EXAMPLES
Example 1. Solid State Sunlight Exposure of Compound A
[0163] Approximately 500 mg of Compound A dry powder was placed in
a 1-gallon polyethylene bag and exposed to sunlight for two months
consecutively during daylight hours. The powder was in a very thin
layer and the bag was shaken often to ensure that all the powder
and not just the top layer was exposed to sunlight. A control
sample of Compound A powder was stored in an amber vial in the dark
for the same amount of time for comparison purposes. After two
months, visual inspection of the two samples indicated that the
light-exposed sample had become off-white, compared to the control
sample which was yellow. The light-exposed sample and the control
sample were analyzed by HPLC to evaluate differences in their
composition. The HPLC method used a reverse phase Zorbax Eclipse
XDB-C8, 3.5 .mu.m, 4.6.times.150 mm column. The mobile phase was
comprised of water and acetonitrile mixtures acidified with
trifluoroacetic acid. Gradient elution with increasing acetonitrile
provided chromatograms of the control sample of Compound A (FIG. 1,
before light exposure) and the light-exposed sample of Compound A
(FIG. 1, after light exposure) with UV detection at 230 nm. The
HPLC of the light-exposed sample shows the appearance of a new
peak, designated as "Photodegradation Product" in FIG. 1.
[0164] Before exposure to sunlight, the Compound A powder had a
purity value of 99.1% as measured by reverse phase HPLC and no
single impurity was present at a level above 0.2% w/w (2000 ppm).
After exposure to sunlight, the Compound A powder had a slightly
lower purity value of 98.4%. After exposure to sunlight, a new peak
appeared in the chromatogram evidencing a new molecule. The new
peak had an area of 0.34%. The fact that the area percent of
Compound A decreased on exposure to sunlight and the new molecule
appeared suggests that a fraction of Compound A is converting to
the new molecule, a photodegradation product.
Example 2. Photostabilizing Coating of Tablet
[0165] It was found that tablets comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid photodegrade upon exposure to light. To reduce the
photodegradation of Compound A in the tablets, various coatings
were tested for their photostabilizing properties.
[0166] Pink/Peach coating formulas tested included a coating
comprising
Formula 1: iron oxide red, iron oxide yellow and titanium dioxide
("Pink/Peach #1"); Formula 2: Sunset Yellow FCF, iron oxide red and
titanium dioxide ("Pink/Peach #2"); or Formula 3: iron oxide red,
iron oxide yellow and titanium dioxide ("Pink/Peach #3").
[0167] The red coating formulas tested included a coating
comprising
Formula 4: Allura Red AC and Indigotine aluminum lakes, and
titanium dioxide ("Allura Red AC/Indigotine"); Formula 5: Allura
Red AC aluminum lake and titanium dioxide ("Allura Red AC"); or
Formula 6: Iron oxide red and titanium dioxide ("Red Iron
Oxide").
[0168] Tablets comprising either 20 mg or 100 mg of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid were coated in an evenly distributed layer with different
amounts of photostabilizing agent per tablet surface area
(mg/cm.sup.2) in a coating pan with reduced lighting. Table 1 lists
examples of tablet coatings at various levels using different
coating formulas. The 3%, 4%, 4.5% or 7.5% coating level is the
percentage of the weight of the coating material over the weight of
the tablet core being coated.
TABLE-US-00002 TABLE 1 Examples of Photostabilizing Agents per
Tablet Surface Area Present in Tablets Coated at Different Coating
Levels 20 mg strength tablet with 3% target coating level For- For-
For- For- For- For- mula mula mula mula mula mula 1a 2a 3a 4a 5a 6a
Total Allura Red AC 0.000 0.000 0.000 0.136 0.123 0.000
(mg/cm.sup.2) Total Indigotine (mg/cm.sup.2) 0.000 0.000 0.000
0.0005 0.000 0.000 Total Sunset Yellow FCF 0.000 0.009 0.000 0.000
0.000 0.000 (mg/cm.sup.2) Red iron oxide (mg/cm.sup.2) 0.008 0.003
0.005 0.000 0.000 0.134 Yellow iron oxide 0.043 0.000 0.005 0.000
0.000 0.000 (mg/cm.sup.2) Titanium dioxide (mg/cm.sup.2) 0.621
0.609 0.661 0.126 0.125 0.639 20 mg strength tablet with 4% target
coating level For- For- For- For- For- For- mula mula mula mula
mula mula 1b 2b 3b 4b 5b 6b Total Allura Red AC 0.000 0.000 0.000
0.182 0.163 0.000 (mg/cm.sup.2) Total Indigotine (mg/cm.sup.2)
0.000 0.000 0.000 0.001 0.000 0.000 Total Sunset Yellow FCF 0.000
0.012 0.000 0.000 0.000 0.000 (mg/cm.sup.2) Red iron oxide
(mg/cm.sup.2) 0.010 0.004 0.007 0.000 0.000 0.179 Yellow iron oxide
0.057 0.000 0.007 0.000 0.000 0.000 (mg/cm.sup.2) Titanium dioxide
(mg/cm.sup.2) 0.828 0.811 0.881 0.168 0.167 0.852 20 mg strength
tablet with 7.5% target coating level For- For- For- For- For- For-
mula mula mula mula mula mula 1c 2c 3c 4c 5c 6c Total Allura Red AC
0.000 0.000 0.000 0.341 0.306 0.000 (mg/cm.sup.2) Total Indigotine
(mg/cm.sup.2) 0.000 0.000 0.000 0.001 0.000 0.000 Total Sunset
Yellow FCF 0.000 0.023 0.000 0.000 0.000 0.000 (mg/cm.sup.2) Red
iron oxide (mg/cm.sup.2) 0.019 0.007 0.013 0.000 0.000 0.336 Yellow
iron oxide 0.107 0.000 0.013 0.000 0.000 0.000 (mg/cm.sup.2)
Titanium dioxide (mg/cm.sup.2) 1.552 1.521 1.652 0.316 0.314 1.598
100 mg strength tablet with 3% target coating level For- For- For-
For- For- For- mula mula mula mula mula mula 1d 2d 3d 4d 5d 6d
Total Allura Red AC 0.000 0.000 0.000 0.240 0.216 0.000
(mg/cm.sup.2) Total Indigotine (mg/cm.sup.2) 0.000 0.000 0.000
0.001 0.000 0.000 Total Sunset Yellow FCF 0.000 0.016 0.000 0.000
0.000 0.000 (mg/cm.sup.2) Red iron oxide (mg/cm.sup.2) 0.014 0.005
0.009 0.000 0.000 0.237 Yellow iron oxide 0.075 0.000 0.009 0.000
0.000 0.000 (mg/cm.sup.2) Titanium dioxide (mg/cm.sup.2) 1.094
1.073 1.165 0.222 0.221 1.127 100 mg strength tablet with 4% target
coating level For- For- For- For- For- For- mula mula mula mula
mula mula 1e 2e 3e 4e 5e 6e Total Allura Red AC 0.000 0.000 0.000
0.320 0.288 0.000 (mg/cm.sup.2) Total Indigotine (mg/cm.sup.2)
0.000 0.000 0.000 0.001 0.000 0.000 Total Sunset Yellow FCF 0.000
0.021 0.000 0.000 0.000 0.000 (mg/cm.sup.2) Red iron oxide
(mg/cm.sup.2) 0.018 0.006 0.013 0.000 0.000 0.316 Yellow iron oxide
0.100 0.000 0.013 0.000 0.000 0.000 (mg/cm.sup.2) Titanium dioxide
(mg/cm.sup.2) 1.459 1.430 1.553 0.297 0.295 1.502 100 mg strength
tablet with 4.5% target coating level For- For- For- For- For- For-
mula mula mula mula mula mula 1f 2f 3f 4f 5f 6f Total Allura Red AC
0.000 0.000 0.000 0.360 0.324 0.000 (mg/cm.sup.2) Total Indigotine
(mg/cm.sup.2) 0.000 0.000 0.000 0.001 0.000 0.000 Total Sunset
Yellow FCF 0.000 0.024 0.000 0.000 0.000 0.000 (mg/cm.sup.2) Red
iron oxide (mg/cm.sup.2) 0.021 0.007 0.014 0.000 0.000 0.355 Yellow
iron oxide 0.113 0.000 0.014 0.000 0.000 0.000 (mg/cm.sup.2)
Titanium dioxide (mg/cm.sup.2) 1.642 1.609 1.747 0.334 0.332
1.690
[0169] The coated tablets were exposed to light (ICH Option 2), and
tested for photodegradation by measuring the amount of
photodegradation product that was present by using reverse phase
HPLC. Dark controls were wrapped in aluminum foil. The reverse
phase HPLC method used to quantify photodegradation product had an
upper quantitation limit of 0.25% or 2500 ppm. Where values above
0.25% or 2500 ppm were reported, a modified reverse phase HPLC
method with a higher upper quantitation limit, but of lower
sensitivity, was used. Tables 2 and 3 show mean values (n=10) of
photodegradation product (in ppm relative to Compound A) for each
red-coated tablet batch tested. "ND" refers to not determined. "NA"
refers to not applicable.
TABLE-US-00003 TABLE 2 Photodegradation of 20 mg Strength Tablet
with Red Coatings Photodeg- Coating radation Level Light Product
Mean Coating Formula (w/w) Exposure Value (ppm) Allura Red AC/
Formula 4a 3% ICH Option 2 1645 Indigotine Formula 4b 4% ICH Option
2 859 Allura Red AC Formula 5a 3% ICH Option 2 1816 Formula 5b 4%
ICH Option 2 859 Red Iron Oxide Formula 6a 3% ICH Option 2 1304
Dark Control 2 Formula 6b 4% ICH Option 2 422 Uncoated NA Dark
Control <2 N/A ICH Option 2 5813
TABLE-US-00004 TABLE 3 Photodegradation of 100 mg Strength Tablet
with Red Coatings Photodeg- Coating radation Level Light Product
Mean Coating Formula (w/w) Exposure Value (ppm) Allura Red AC/
Formula 4d 3% ICH Option 2 241 Indigotine Formula 4e 4% ICH Option
2 68 Allura Red AC Formula 5d 3% ICH Option 2 151 Formula 5e 4% ICH
Option 2 37 Red Iron Oxide Formula 6d 3% ICH Option 2 52 Formula 6e
4% ICH Option 2 8 Uncoated N/A ICH Option 2 2962
[0170] These results are depicted graphically in FIG. 2A (20 mg
strength tablet) and 2B (100 mg strength tablet).
[0171] Photodegradation results for tablets coated with pink/peach
formulas at the 3% or 4% coating level (based on the weight of the
tablet core), after exposure to ICH Option 2 conditions are shown
in FIG. 3A and Table 4 for the 20 mg strength tablets, and in FIG.
3B and Table 5 for the 100 mg strength tablets.
TABLE-US-00005 TABLE 4 Photodegradation of 20 mg Strength Tablet
with Pink/Peach Coatings Photodeg- Coating radation Level Light
Product Mean Coating Formula (w/w) Exposure (ppm) Pink/Peach #1
Formula 1a 3% ICH Option 2 .gtoreq.2500 Dark Control 2 Formula 1b
4% ICH Option 2 2079 Pink/Peach #2 Formula 2a 3% ICH Option 2
.gtoreq.2500 Formula 2b 4% ICH Option 2 .gtoreq.2500 Piiik/Peach #3
Formula 3a 3% ICH Option 2 .gtoreq.2500 Formula 3b 4% ICH Option 2
.gtoreq.2500
TABLE-US-00006 TABLE 5 Photodegradation of 100 mg Strength Tablet
with Pink/Peach Coatings Photodeg- Coating radation Level Light
Product Mean Coating Formula (w/w) Exposure (ppm) Pink/Peach #1
Formula 1d 3% ICH Option 2 889 Formula 1e 4% ICH Option 2 115
Pink/Peach #2 Formula 2d 3% ICH Option 2 1173 Formula 2e 4% ICH
Option 2 608 Pink/Peach #3 Formula 3d 3% ICH Option 2 1885 Formula
3e 4% ICH Option 2 1138
Example 3. Photostabilizing Gelatin Capsule
[0172] Compound A in gelatin capsules also exhibits
photodegradation upon light exposure. Gelatin film coatings
containing various dye combinations were tested for their
photostabilizing properties.
[0173] Gelatin capsules comprising
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid in colorless transparent hard gelatin capsule shells were
covered with a gelatin film comprising various photostabilizing
agents, exposed to light under ICH Option 2 described herein, and
tested for photodegradation of
[(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic
acid by measuring the amount of photodegradation product using
reverse phase HPLC described in Example 1. Results represent the
mean value of photodegradation product measured in 10 capsules.
[0174] The composition of the hard gelatin films tested is shown in
Table 6 below.
TABLE-US-00007 TABLE 6 Gelatin Films % w/w (based on weight
Ingredient of capsule shell) Orange #1 Yellow iron oxide 1% Allura
Red AC 0.3%.sup. Titanium dioxide 1% Orange #2 Yellow iron oxide 1%
Red iron oxide 0.7%.sup. Allura Red AC 0.3%.sup. Titanium dioxide
1% Orange #3 Yellow iron oxide 1% Red iron oxide 1% Titanium
dioxide 1% Red #1 Red iron oxide 2% Titanium dioxide 1% Yellow
Yellow iron oxide 2% Titanium dioxide 1% Orange #4 Yellow iron
oxide 1% Allura Red AC 1% Titanium dioxide 1% Blue Indigotine 1%
Titanium dioxide 1% Red #2 Red iron oxide 2% Titanium dioxide
0.9%.sup.
[0175] As shown in Table 7 and FIG. 4, the orange dyes offered the
best photostabilization of Compound A in the hard gelatin
capsules.
TABLE-US-00008 TABLE 7 Photodegradation of Hard Gelatin Capsules
Containing Compound A Photodeg- radation Product Mean Gelatin Film
(ppm) Light Control (No 10563 Gelatin Film) Orange #1 378 Orange #2
96 Orange #3 619 Red #1 1500 Yellow 1194 Orange #4 247 Blue 6100
Red #2 1432
* * * * *