NZ714554B2 - Pharmaceutical formulations of a hif hydroxylase inhibitor - Google Patents

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 in the treatment of e.g. anemia. The formulation comprises a coating comprising titanium dioxide and a dye which stabilises [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid from light-induced degradation. xy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid from light-induced degradation.

Description

PHARMACEUTICAL FORMULATEONS OF A HIF HYDROXYLASE INHIBITOR CROSS REFERENCE TO RELATED AP?LECATIONS {0001! This application claims the benefit under 35 U.S.C. § 1 19(e) of United States Provisionai Application 6i/831,909 filed June 6, 2013 and is hereby orated by reference in its entirety.

BACKGROUNI) {8082] The present invention relates generally to pharmaceutical formulations of {(4—hydroxy— l » methyi-7—phenoxy-isoquinoiinefi-catbonyI)—atninD]-acetic acid. {@003} {(4—Hydroxy-l-n1ethyl—7~phenoxy—isoquinoiine~3carbonyl)—amino}~acetic acid (alternativeiy referred to herein as Compound A} is a potent inhibitor of hypoxia ble factor (iiiF) prolyl hydro-xylase, as described in US! Patent No. 475. i-liF proiyi hydroxylase inhibitors are useful for increasing the stability and/or activity of HlF, and useful for, inter alia, treating and preventing disorders associated with HIF, ing anemia, and ischemia- and hypoxia—related disorders. {$004} it has recently been discovered that Compound A undergoes decomposition after exposure to light. tofore, pharmaceutical foi'mniations of Compound A which provide the necessary photostability of the compound have not yet been .

SUMMARY [0965} The present disciosure fulfills the need of providing photostability of Compound A and others by providing a pharmaceutical fOl‘intliatiOIl comprising [(4—hydroxy—i—methyl--7~phenoxy~ isoquinoline—3~carhonyl)-amino]~acetic acid, a ceuticaily acceptable excipient and an effective amount of a photostztbilizing agent. In one embodiment, the pharmaceutical formulation comprises less than about 0.2% w/w (based on the amount of active ceutical ingredient {“API”)) pilotodegradzition product of {(4-nydroxy~1—methyi~7«phenoxy~isoquinoiine~3—carbonyi)-amino}- acetic acid. in another embodiment, the photostabilizing agent blocks light at a wavelength range of between about 200 and about 550 Inn, {0006} in one embodiment, the tabilizing agent comprises titanium dioxide and at least one additional dye, In one ment, the photostahilizing agentbiocks light at a wavelength range of [Annotation] wilksar None set by wilksar [Annotation] r MigrationNone set by r [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] r MigrationNone set by wilksar [Annotation] r Unmarked set by wilksar between about 200 and about 550 nm. In one embodiment, the dye is selected from the group consisting ot'a black dye, a blue dye, a. green dye, a red dye, an orange dye, a yellow dye, and combinations f. in another embodiment, the dye is selected from the group consisting of a red dye, an orange dye, a yellow dye, and ations thereof. {8837] in one embodiment, the dye is ed 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, lndigotine, lndigotine aluminum lake, and combinations thereof. {9068! in one embodiment, the pharmaceutical formulation comprises from about 20 mg to about 200 mg of [(4rhydr0xy-l~methyl-7—phenoxy—isoquinoline~3-carbonyl)~amino]~acetic acid. in another embodiment, the pharmaceutical formulation comprises about 20 mg, about 50 mg, or about lOG mg of [(4al1ydroxy—l~methyl—7mphenoxynisequinoline~3-carbonyllamina—acetic acid. {0009} in one embodiment, a solid dosage form ses the pharmaceutical formulation and the solid dosage form is ed from a capsule, tablet, head, granule, pellet, lozenge, pill, or gum. In. another ment, the solid dosage form is a tablet. In another embodiment, the solid dosage form is a capsule, {0916} The present disclosure provides a tablet comprising [(4—hydroxy- l --metliyl—7—pltenoxy— isoquinoline—S~carbonyl)~aminoluacetie acid, a pharmaceuticaliy acceptable excipient and an etl’ective amount of a photostabilizing agent. in one embodiment, the tablet comprises a tablet core and a coating. In some embodiments, the photostabillzing agent is blended into the tablet or the tablet core.

In other embodiments, the tablet core comprises droxy~- l -methyl-7—phenoxy—isoquinoline—3- carbonyl)-amino}—acetic acid and the phannaceutieally acceptable exeipient, and the coating comprises the photostabilizing agent. {00111 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-l1ydroxy—l~methyl~7-phenoxy-‘isoquinolineu3— earbonyl)—amino]-acetic acid (based on the weight ofthe tablet core). in yet another embodiment, the phannaceutically acceptable excipient comprises lactose monohydrate, rystalline cellulose, povidone, croscamtellose sodium, and ium 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 [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by r [Annotation] wilksar Unmarked set by r [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar comprises titanium dioxide and at least one additional dye selected from the group consisting of Allure Red AC, Allure Red AC aluminum lake, iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow FCF aluminum lake, Indigotine, l'ndigotine aluminum lake, and combinations thereof. in another embodiment, the photostabilizing agent comprisestitanimn dioxide and Allura Red AC aluminum lake. {0813} The t disclosure provides a capsule comprising [(ti—hydroxy- l—methyl—"f—pltenoxy- isoqoinoline«3~carbonyl)uamino]acetic acid, a ceuticaliy acceptable excipient and an effective amount of a nitotostabilizing agent. in one ment, the-capsule comprises a capsule fill and a capsule shell. In one ment, the capsule till comprises {(4—hydroxy~i “methyl—7~phenoxy~ isoqninoline—3~carhonyl)uemino}—acetic acid and the pharmaceutically acceptable cxcipi‘ent, and the e shell comprises the photostabilizing agent. {9014} In one embodiment, the capsule fill comprises from about 12% to about l5% w/w {(4— hydroxy~l “methyl—lobenoxy-isoquinolinc—3-carbonyl}—amino]~acetic acid (based on the weight of the capsule fill). in another embodiment, the pharmaceutically able excipient comprises lactose monohydrate, microcrystaiiine cellulose, nc, croscarrnellose sodium, and magnesium stem-ate. [0015} In one embodiment, the capsule shell ses the photostabilizing agent in an amount of from about 1.8% to about 6% w/w (based. on the weight ofthe capsule shell). in some embodiments, the photostebilizing 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 photodegradetion of droxy—l~ inethyi—7~pltenoxy—isoquinoiine~3~carbonyl)-amino}—acetic acid is provided. The method ses formulating {(4-hydroxy-i ~meti1ylphenoxy—isoquinolineu3-carhonyl)«amino]«acetic acid with an effective amount of a tabiiizing agent. in another ment, the photostahilizing agent comprises titanium dioxide and at least one additional dye, {9017} in yet another embodiment, a method for treating, preheating, or delaying onset or progression of'a condition mediated at least in part by hypoxia inducible factor (HIP) is provided.

The method comprises administering to a patient. in need thereof, a pharmaceutical formulation, 3 tablet, or a capsule as described herein. ation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by r {6018] In still yet another, embodiment, a method for treating, preheating, or delaying onset or progression of anemia is provided. The method comprises administering to a patient in'need f, a pharmaceutical formulation, a tablet, or a capsuleas described herein.

BRIEF DESCRIPTION OF THE DRAWINGS [0919} illustrates the HPLC chromatograms ofCompound A powders before and after exposure to sunlight. See Example l for details. {0320} and 2B illustrates the amount of pliotodegradation product in tablets containing either 20 mg (PEG. 2A) or 100 mg (FlG. 28) ofCompound A upon light re. The tablets are. coated with a coating formula ning Allure Red AC/lndigotine ititanium dioxide (labeled as Allure. Red AC/indigo’tine in figures}, Allura Red AC/titaniurn dioxide ed as Allura Red AC in figures), erred iron titanium dioxide (labeled as Red Iron Oxide in figures). See Example 2 for details. {8021] and 38 illustrates the amount of photodegradation t in tablets containing either 20 mg () or 100 mg (FIG. SB) of nd A upon light exposure. The tablets are coated with a variety of each coating formulas. See Example 2 for details. {09.22} demonstrates the amount of photodegradation t in capsules covered wiih gelatin films containing various photostabilizing agents upon light exposure. See Example 3 for details.

DETAILED DESCRIPTION Definitions {9023] As used herein, the following terms have the following meanings. {30243 The singular forms “a,” “an,” and “the” and the like include plural referents unless the t clearly dictates otherwise. Thus, for example, reference to “a compound” includes both a single compound and a plurality of different compounds.

[Annotation] wilksar None set by wilksar ation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] r None set by wilksar ation] wilksar ionNone set by r [Annotation] wilksar Unmarked set by wilksar {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 230%, 325% or {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 s.

Although any methods and materials similar or equivalent to those described herein can he used in the practice or testing ofthe present invention, the preferred methods, devices, and materials are now bed. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methodologies, ts, 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, log and ceutical sciences, within the skill of the art. Such techniques are explained fully in the literature. (See, eg, o, A.R., ed. (1990) ton’s Pharmaceutical Sciences, 18m ed, Mack Publishing Co.; Colowick, S. e: (21,, eds, Methods in Enzymology, ic Press, Inc; DM. Weir, and QC. Blackwell, eds. (1986) Handbook of mental immunology, Vols. l—lV, Blackwell.

Scientific Publications; Maniatis, T. at 521., eds. ( l 989) Molecular Cloning: A Laboratory Manual, 2“d edition, Vols. l-lll, Cold Spring Harbor Laboratory Press; Ausubel, F. M. et (21., eds. ( l 999) Short Protocols in Molecular Biology, 4"“ edition, John Wiley & Sons; Ream of mi, eds. (1998) Molecular Biology Techniques: An Intensive Laboratory Course, Academic Press; Newton 8:. Graham eds.

(P997) PCR (Introduction to Biotechniques Series), 2nd ed, Springer Verlag; European Pharmacopoeia (Pli. Eur), 7m edition; The United States Pharmacopeia (USP) and the National Formulary (NF), USP 35 w NF 30. [8928} The term “API” is the abbreviation for “active phamtaceutical ingredient.” As used herein, APE refers to Compound A, or [(4»hydroxy~l «methyl»?-phenoxy—isoquinoline«3~carbonyl)—arnino}- acetic acid.

[Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] r Unmarked set by wilksar ation] wilksar None set by wilksar [Annotation] r MigrationNone set by wilksar [Annotation] wilksar ed set by wilksar [0029} The term “block light” refers to preventing 0r reducing the transmittance of light by absorbing, reflecting, retracting, 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, ing, retracting, diffracting, dispersing, and/or scattering light. {8030} The term “capsule” refers to a solid dosage form of a pharmaceutical formulation that comprises a e shell and a e fill. [00315 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 ofAPl in the capsule till can be expressed as a weight percent of APlvbased on the total weight ofthe capsule fill . {0032'} The term “capsule shell” refers to an outer layer ol‘a capsule- The capsule shell ses gelatin, cellulose polymers or other suitable als 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 ~—shell_ed capsules are typically used to deliver dry, powdered API in the capsule fill. The capsule shell may he a one~piece hell used to deliver AM as a on or suspension in the capsule fill. in one embodiment, the capsule shell may comprise the photostahilizing agent. The amount of photostahilizing agent in the capsule shell can he expressed as a weight percent of photostabilizing agent based on the total weight ofthe capsule shell (%w/w). in one embodiment, the capsule shell comprises gelatin (a. gelatin shell). in another embodiment, the e 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 t 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 e they absorb light in the visible spectrum (400400 um) and transmit, reflect or scatter light of other wavelengths in the visible spectrum. A “yellow dye” absorbs [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar ation] wilksar None set by r [Annotation] r MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar 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 reeri 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” absrrrbs light ofthe entire visible speclmm and appears black in color. Examples ofrecl (lye, 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, reliactlng, diffractiog, 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. {£3036} Dyes bed 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 Cl name (Color index name). Non- limi‘ting examples of dyes are listed in the following table.

E Color Principal Name hUS Nahie ‘u__“CIE§—rr1o g E White dye “ m““““““““““““““““for Titanium e Pigment White 6 Beige dye Caramel C.I. l Brown ll) 5 """""l‘reeeeg‘a‘za AlluraREE—if" Allura Red AC i Amaranth Cl. Food Red 9 or. Food lied 3 Cl. Food Orange 8 D&C Red 33 D&C Red 33 CI. Food Red l2 *‘‘‘‘‘‘‘ Eosine YS C.l. Food Red 8‘7 Erylthrosine FD&C Red 3 {dye C3. Food Red l4 only} iron oxide red or [ or. Pigment Red 101 & Red iron oxide i 102 . l Red dye Lithol Rubine BK 9&0 Red 7 [Annotation] r None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar E Red dye E Phloxine B 0&0 Red 28 : “fl”"75??de"""""""E Ponceau 4R E I E m__________________________“ ..._....“..V.V..__.__..._—_.__________ Red dye E Red 20 l (LI. Food Red 10 -----------------E______________________________________W ----------E Yellow dye W (3.1. Food Orange 5 E Ye?low dye ngé--------------E~~~~~~~~~~~~ Cl. Food Orange 5 E Yellow dye Cureumin E (2.1. Natural Yellow 3 E . _ ______“ Yellow dye D&C Yellow 10 D&C Yellow l0 (ll. Food Yellow l3 Yellow dye Iron oxide yellow or l CI. Pigment Yellow E Yellow iron oxide E 42&43 -_“lailfooline Yellow WS WE Cl. Food Yellow 13 Yellow dye Riboflavin E . “—4 Yellow dye Sunset Yellow FCF Cl. Food Yellow 3. E Yellow dye zine (3.1. Food Yellow 4 E Green dye Chlorophylls and (1.1. Nantral Green 3 E Chlorophyllins Cu Complexes of Cl. Natural Green 3 Chlorophylls and Chlorophyllins “"““““““ Fa“ Green FCF E‘FDZ‘QC Green 3 Cl. Food Green 3 ” --------------- Green dye Green S C1. Food Green 3 Blue dye Brilliant Blue FCF FD&C Blue 1 C3. Food Blue 2 Blue dye Indigotine FDé’aC Blue 2 C1. Food Blue 1 Blue dye Patent Blue V Cl. Food Blue 5 “EEEE‘E§é“M””””"' emmeee"""""""" "_ C.l. Food, Black 1 Black dye Iron oxide black Cl. Pigment Black ll (or Black iron oxide) BEE}; dye ' Vegetable Carbon (3.1—.Food Black 3 [0637} The term “pharmaceutically acceptable” indicates that the material does not operties 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 lobe treated and the respective route of stration. .

Further, the material is considered to be safe for stration in humans or animals.

[Annotation] wilksar None set by wilksar [Annotation] r MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [0038} The term ient” or “pharmaceutically acceptable excipient” refers to pharrnacologically inactive substances that are added to a pharmaceutical preparation in addition to the active pharmaceutical ingredient, Exeipients may take the function of vehicle, t, release, egration or dissolution ing agent, absorption enhancer, stabilizer or a manufacturing aid among others; Excipienls may e fillers (diluents), binders, disintegrating agents, lubricants, and glidants. Examples of excipient classes frequently used are listed below. {0839] nt or filler” refers to substances that are used to dilute the active pharmaceutical ient prior to delivery. ts can also serve as stabilizers. Non—limiting examples of diluents include starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, liydroxypropyl cellulose, sugar ls, l, sorbitol, tcl, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, (libasic calcium phosphate dehydrate, mannitol, microcrystalline cellulose, and tribasic calcium phosphate. {9048} “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 ers 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 alter administration and permits the e of an active ingredient as efficiently as possible to allow for its rapid dissolution. Non~limiting examples of disintegrnnts include maize starch, sodium starch glycoiate, rmellose sodium, crospovidone, microcrystaliine cellulose, modified corn , sodium carhoxymethyl starch, povidone, pregelatinized starch, and alginic acid.

“Lubricant” refers to an excipient which is added to a powder blend to prevent the compacted powder mass from sticking to the ent during the tableting (tr-encapsulation process.

It. aids the ejection cftlie tablet form the dies, and can improve powder flow. Non~limiting examples of ants includemagnesium stenrate, stearic acid, silica, fats, calcium stearale, polyethylene glycol, sodium stearyl te, talc, or fatty acids including lauric acid, oleic acid, and (L’s/Cw fatty acid. {0943} “Glid‘ant” as used herein is intended to mean agents used in tablet and capsule fonnulations to improve flow—properties during tablet compression and to produce an anti-coking effect. Non— [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar ation] wilksar Unmarked set by wilksar ation] wilksar None set by wilksar [Annotation] r ionNone set by r [Annotation] wilksar Unmarked set by wilksar limiting examples of ts include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and ite. 19644} The term “formulate” or “formulating” refers to combining the active phannaceutical 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 ofmedicinal product include, but not limited to, tablets, pills, s, capsules, gels, syrups, siurries, suspensions, aerosol sprays, and solutions for injection. {9945} The term “gelatin” refers to a solid substance derived from collagen and can be obtained from various animal lay—productions. it is commonly used as a gelling agent in pharmaceuticals. {80465 The term “light exposure”, refers. any light exposure, including sunlight (or natural light), indoor light and exposure to light under ational Conference of ization (ICH) conditions. “lCl-l light exposure” means exposure to light under lCH conditions, which may be lCH Option l. or lCH Option 2. Under {CH conditions, the samples are exposed to light providing an overall illumination of not less than 2.2 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 ole). a. lCl-i Option 2: Any light source that is designed to produce an output. similar to the 65 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 l0977 (1993), H365 is the equivalent indoor indirect daylight standard. For a light source ng significant radiation below 320 nanometers (run), an appropriate filter{s)- may be fitted to eliminate such ion. 1). ICE Option 2': A cool white cent lamp designed to produce an output similar to that specified in 130 i097? (1993); and [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar A near UV fluorescent lamp having a spectral bution 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 run and 360 to 400 run. {0047] The term “photostalailizing agent” is an agent that prevents or reduces the egredation or photodecomposition of a molecule upon exposure to light (light under {CH condition, sunlight, indoor light, etc.). in other words, the photostahilizing agent ons to prevent or reduce the formation ofphotodegradation products. Typically, the photostabilizing agent prevents or reduces the photodegradation of the light~sensitive molecule by ng the exposure of the molecule to light within a. ngth range. Non-limiting examples of photostabilizing agents include pigments, dyes, dye lakes, and the like. [6048} The term “pholodegradation” and “photodecomposition.” are used interchangeably hout the disclosure. 10049} The term tive amount” of a photostabilizing agent refers to the amount ofa photostabilizing agent in a pharmaceutical ation that is ient to prevent or reduce the photodegradation of the active pharmaceutical ingredients (AFl), such that the amount of photodegradation product(s) that is produced is limited to a desired maximum level under ed 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 lCH conditions. in some embodiments, the effective amount ot‘photostabiiizing agent may limit the amount of photodegradation product of Compound A that is produced to a level that is less than about 0.25% w/w Compound A, less than about 0.1% wz’w Compound A, or less than 0.05% w/w nd A. As will be apparent to one skilled in the formulations art, the eftective amount of a stabilizing agent will vary with the particular agent used. Using the disclosure herein, particularly the analytical methods bed in the examples, and the l 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 ot‘photoprotection (i.e., reduction ot‘the production of photodegrad'ation product) sufficient to limit photodegradation product to the desired maximum level. {0050} 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., erformance liquid chromatography [Annotation] wilksar None set by wilksar [Annotation] r MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar (HPLC), liquid chromatography-mass spectrometry (LC—MS), gas chromatography (GC), nuclear magnetic resonance (NMR), r transform infrared spectroscopy (FTlR), etc). in one embodiment, the photodegradation product may be detected and measured by i—IPLC, as further described in Example l. {8651] The term “tablet” refers to a soiid dosage form of a pharmaceutical formulation in which the API is blended with one or more pbarmaceutically acceptable excipient and compressed into a single solid final. dosage form. s can be produced in a wide variety of sizes, shapes, and surface markings. s may be tmccated or coated by a variety oftechniques that are Well known in the art. Typically, a tablet comprises a tablet core and a coating. {0052} The. term “tablet core” refers to the inner part of a tablet containing the AP! and one or more phamtaceutically able exeipient compressed into the desired shape but not including the coating. The amount ofAM in the tablet core can he expressed as a percent ot‘APl by weight based on the total. weight of the tablet core, %,w1’w. [0053} The term “coating" refers to an outer part of a tablet. For tablets as described herein, the coating is applied to the outer surface ofthe tablet core and typically s thereto. The coating may provide one or more of the following properties: taste masking, protecting the APKS) from photodegradation, ease of administration, release modification ofthe APKS), dust protection, or unique appearance (colors), tong other things. Nonwlirniting examples of coating materials include polyvinylalcohol—based nds, hydroxyetliylcellnlose, hydroxypropylnietnylcellulose, carboxyrnethylcellulose sodium, polyethylene glycol 4000. and cellulose e 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 sed as a percent ofcoating by weight based on the weight of the tablet core, % wfw. in one embodiment, the coating may se 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 ot‘tlte dye d per surface area unit of the tablet core, mg/cmg. {0054} 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 ated with abnormal tion, sing, or performance of erythrocytes andj‘or obin. The term anemia refersto any reduction in the number ofred blood cells andlor level of hemoglobin in blood relative to normal blood levels. Anemia can arise due to conditions such as acute or chronic kidney disease, infections, [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar ation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar 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, mune disorders, such as rheumatoid arthritis, etc. Anemia can also be associated with blood loss due to, egg, stomach ulcer, duodenal ulcer, hemorrhoids, cancer of the stomach or large intestine, trauma, injury, al procedures, etc. Anemia is further associated with ion therapy, chemotherapy, and kidney dialysis. Anemia is also associated with HiVuinfected patients undergoing treatment with azidothymidine (zidovudine) or other reverse transeriptase inhibitors, and can develop in cancer patients undergoing chemotherapy, e.g, with cyclic cispiatin~ or spiatin~containing chemotherapeutics. Aplastic anemia and inyeiodysplastic syndromes are diseases associated with bone marrow e-that result in decreased production of erythrocytes. Further, anemia can resuit from defective or abnormal hemoglobin or erythrocytes, such as in disorders ing microcytic anemia, hypochromic anemia, etc, Anemia can result from disorders in iron ort, processing, and utilization, see: ag, siderobiastic anemia, etc. {0055} The terms “disorders,” “diseases,” and tions" are used inclusively herein and refer to any condition deviating from normai. {9056} “Treatment”, “treating”, and “treat” are defined as acting upon a disease, disorder, or ion with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and/or its ms, Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of ence ofthe condition in a patient determined to be posed to the disease but not yet diagnosed as having the condition, (is) impeding the development of the condition, andfor (c) relieving the» condition, to, causing regression ofthe condition and/”or relieving one or more symptoms ofthc condition. [0857} “Administration” refers to introducing an agent into a patient. A therapeutic amount can he 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 istering” and “administration of”, when used in connection with a compound or ceutical formuiation (and grammaticai 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 he the act of prescribing a. drug. For example, a physician who instructs a patient to self- administer a drug and/or es a patient with a prescription for a drug is administering the drug to the patient. in any event, administration entails delivery ofthe drug to the patient.

[Annotation] wilksar None set by wilksar [Annotation] r MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] r None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] r Unmarked set by wilksar Hypoxia inducible factor (HIP) is a basic helix—loop-helix (bHLi-l) PAS (Per/Arnt/Sim) riptional activator that mediates changes in gene expression in response to changes in ar oxygen concentration. HIF is a heterodimer containing an oxygen—regulated (I-Sllbuni‘i (HlFo), and a constimtively expressed Busubonit (HiFB/ARNT). In oxygenated (normoxic) cells, l-lch subunits are rapidly degraded by a mechanism that involves ubiquitinafion by the von HippeI~Lindau tumor suppressor (pl/EL} E3 ligase complex. Under hypoxic conditions, HIFa is not degraded, and an active i‘ilFolfl complex lates in the nucleus, and activates the expression of several genes including glycolytic enzymes, glucose orters, erythropoietin (EPO), and vascular endothelial growth factor ; (Hang et al. 0996) J. Biol Chem. 271 : l777l— 17778; ulus et al. (l 996) Proc. Natl; Acad. Sci. USA, 933059540599; Maxwell et all (1999) Nature 14275; Setter et a1. (2000) Proc. Natl. Acad, Sci. USA 84753; Coekman et al. (2000) J, Biol; Chem. 27525733- 253”“; and Tanimoto et al. (2000) EMBO J. 19:42.98-4309.) [0059} The terms “HlF—associated conditions” and “conditions mediated at least in part by l-ilF'“ are used inclusively and refer to any condition that can be associated with below normal, abnormal, or inappropriate modulation, oleF. illF~associated conditions include any condition n an increase in HIF level would provide therapeutic benefit. ssociatcd conditions include anemic» conditions and tissue damage or disorders associated with ischemic or hypoxic conditions. {0069} The terms “HIP prolyl hydroxylase”, “PHD”, “EGLN”, and “Hi? PH” refer to any enzyme that modifies the alpha subunit of l-llF protein by llydroxylation of one or more proline residues. HlF PH includes members of the Egl—Ninc (EGLN) gene family described by Taylor (2001, Gene 2752125432), and characterized by Aravind and Koonin , Genome Biol 2: RESEARCH 0003’), Epstein et a1. (2001, Cal! 107:43-54), and Bruick and McKnight (2001, Science 294: 1337-4340). HIP Pl—l2, as used in exemplary assays described herein (infia), may be any HIF PHZ, also referred to as PHDIZ, e.g., human EGLNI (GenBanlt Accession No, AAGB‘3965; Dupuy et al. (2000) Genomics 69348—54), mouse EGLNI (GenBank Accession No. CAC425 i 5), rat EGLN! (GenBank Accession No. P597222), etc. Alternatively, another lllF l3H may be used in the assay. Such HI? PH enzymes include, but are not limited to HlF Pill, also referred to as PHDl, e.g~., human EGLN2 isoform 1 (GenBank Accession No. CAC42510; Taylor, supra), human EGLNB isoform 3 (GenBank Accession No. NP_542770), mouse EGLNZ (GenBank Accession No. CAC4251‘6), and rat EGLNZ (GenBank Accession No. AAO46039), etc; and any HIP PH3, also referred to as PDHS, eg. human EGLN3 (GenBank ion No. CAC425l 1; , supra), mouse EGLN3 (GenBank Accession No.

CAC42517), and rat EGLNS (SM~2G) (GenBank Accession No.AAA1932i). In other embodiments ofthe present disclosure, EGLN may include Caenorfmbdiris elegans EGL-9 (GenBank Accession [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by r [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar No. AAD56365) and Drosophiz’a melanogasier CG! 1 14 gene product (GenBank ion No.

AAF§2050).

Pharmaceutical Formuiations {6061] The compound Kai-hydroxyulmethyl-7—phenoxy—isoquinoiine~3carbonyl}amino}-acefic acid (Compound A) is a potent inhibitor of hypoxia indocibie factor (HiF) proiyl hydroxylase and has the following formuia: Q EV w(i:' OH /N 0 nd A. {0062} Asdcscribed in the exampies herein, it has recently been ered that nd A undergoes ccomposition after light exposure to convert to a pliotodegradation product, The present invention es compositions (formulations) and methods that prevent or reduce the amount of photodegradation oi‘Compouud A and limitthe amount of egradation product. {0663} The pharmaceutical formulations described herein protect Compound A. from photodegradation. Accordingly, in one embodiment the invention provides a ceutical formulation comprising {(4-hydroxy~l «mothylflmhenoxy—isoquinoiine—3—carbonyi)-amino}~'icetic- acid, a phamiaceuticaiiy acceptabie excipient; and an effective amount of a photostabilizing agent. In a further embodiment, the invention es a pharmaceuticai formuiation comprising droxy- 'l ~mcthyl~7-phenoxy—isoquincIine-B-carbonyi)-omino]«acetic acid, a pharmaceuticaliy acceptabie excipient, and an effective amount of a photostabiiizing agent, wherein the pharmaceutical formulation comprises less than about 0.2% w/w (based on the amount ofAPI, [(4-ildeOXY-i methyl.— 7~phcnoxy—isoquimime-3"carbonyD-amino}uzicct'ic acid) egraoation product of [(4—hydmxy—1- mothYi~7— henoxP y~isoC!uinoliue~3~ear‘oonyl)—amino}—acetic acid.. {9064'} In one embodiment, the phannaceu’ticei formulation comprises iess than about 0.2% wfw (equivalent to 2000 ppm, based on the amount of AP!) photodegradation product of [(4—i1ydroxy-l— inctliyi-7«pltenoxy—isoquinolincul‘»~corbonyi)«amino]aacetic acid after exposure of the formuiatiou to light under ICH conditions. The amount of photodegradation product can be readily determined by ation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] r Unmarked set by wilksar [Annotation] wilksar None set by wilksar ation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar one of ry skill in the art based on the disclosure herein using routine analytical methods. if multiple detemiinations of the amount ofphotodegradation product are made, the mean value of the amount of photodegradation product from multiple determinations is no more than about 0.2% w/w.

The condition ofthe light exposure (the kind of light source, the power ofthe light source and the duration of light exposure) is the lCl—i condition defined . The amount of photodegradation product that is produced is readily determined by the methods described herein, particularly by HPLC method. One d in the formulations art can readily determine the effectiveamount of photostabilizing agent sufficient to limit the amount ofthe egradation product, based on the guidance and examplesprovided herein. [0865} in one embodiment, the photostabilizing agent is selected to prevent or reduce photodegradation of nd 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 ng light in. the ngth 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 es a pharmaceutical formulation comprising {(4—hydroxy—i—methyl—7—phenoxy—isoquinoline—31~carbonyl)~amino}eacetic acid, a pharmaceutically acceptable excipient, and an effective amount of a photostabilizing agent, wherein the photostabilizing agent comprises titanium e and at least one additional dye. in one embodiment, the dye blocks light at a wavelength range of about lDG to about 800 run, about 150 to about 700 run, about 200 to about 550 nm, or about 360 to about 440 not. {0866] 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 onal 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 ofa 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. {0067} in another ment, 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 ofearotenes, Curcumin, Sunset Yeilow FCF, Sunset [Annotation] r None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar ation] wilksar None set by wilksar [Annotation] wilksar ionNone set by wilksar [Annotation] wilksar Unmarked set by wilksar Yellow FCF aluminum lake, zine, chloropliylls and chlorophyllins or Cu complexes thereof, Fast Green FCF, Brilliant Blue FCF, lndigotine, lndigotine aluminum lake, and combinations thereof. {8068] 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, Allure Red AC aluminum lake, Carmine, Erythrosine, beta~carotene or mixtures of carotenes, Sunset Yellow FCF, Sunset Yellow FCF um lake, ehloropltylls and chlorophyllins or Cu complexes thereof, Fast Green FCF, Indigotine, lndigotine aluminum lake, and combinations f. [0669} 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, Allure Red AC aluminum lake, Carmine, beta—carotene or mixtures of carotenes, Sunset Yellow PCP, Sunset Yellow FCF aluminum lake, Indigotine, lndigotine aluminum lake, and combinations thereof. [0070} in another embodiment, the additional dye is selected from the group consisting ofAllura Red AC, Allura Red AC um lake, iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow FCF aluminum lake, lndigotine, Indigotine aluminum lake, and combinations thereof. [0071} In one embodiment, the photostabilizing agent comprises titanium dioxide and Allure 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 ses 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 ment, the photostabilizing agent ses iron oxide yellow and titanium e. {8072-} In some embodiments, the photostabllizing agent comprises titanium dioxide. in some embodiment, the photostabilizing agent comprisesa 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 pliotostaliilizing agent comprises a dye selected from the group ting ofa black dye, a blue dye, a green dye, a red dye, an orange dye, a yellow dye, and combinationsthereofi in yet r embodiment, the photostabilizing agent comprises a dye selected from the group ting of a red dye, an orange dye, a yellow dye, and combinations thereof.

[Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar ionNone set by wilksar [Annotation] wilksar Unmarked set by wilksar {0073] In one embodiment, the pliotosiabilizing agent comprises a dye selected from the group consisting of Caramel, iron oxide black, iron oxide. red, iron oxide yellow, Allura Reel AC, Allura Red AC aluminum lake, Carmine, Eiytlirosine, betaucarotene 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 PCP, lndigotinc, lndigotine aluminum lake, and combinations f. [9074} in one embodiment, the phannaceutical formulation comprises from about 1 mg to about 400 mgof [(-4~hydroxy«lvmetliyl~7—phenoxy~isoquinoline-3nearbonyl)-amino]-acetic acid. In another embodiment, the pharmaceutical ation comprises from about 20 mg to about 200 mg of [(4— hydroxy—i ~m-ethyl~7—phenoxy~isoquinoline—3~carbonyl)-ainino}—acetic acid. in another embodiment, the pharmaceutical formulation comprises about l mg, about 5 mg, about l0 mg, about 15 mg, about mg, about 25 mg, about 50 mg, about 75 mg, about lOO 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-liydroxy— lamethyl—Z"—pbeooxy~isoquinolineu3—carbonyl)~amino]acetic acid. in yet another embodiment, the pharmaceutical formulation ses about 20 mg, about 50 mg, or about lOl) mg of E(4—bydrox>~l- methyl~7-phenoxy«isoquinoline~3«carbonyl)~arnino]acetic acid. in yet another embodiment, the pharmaceutical ation comprises about 20 mg, or about 50 mg of droxy~l~in~etbyls7— y-isoquinoline~3warbonyl)—amino}sacetic acid. {6075] In one embodiment, the pharmaceutical formulation comprises from about 1% to about 90% w/w [(4«hydroxy~lanethyl—7~pbenoxy~isoquinolinc-3—carbonyl)«amlno]—acetic acid. in r embodiment, the pharmaceutical fonnulation ses from about 0.1% to about 50% w/w photostabilizing agent. In another embodiment, the» ceutical formulation comprises from about 1% to about 7% w/w photostabilizing agent. in each embodiment, the pharmaceutical formulation comprises a pharmaceutically acceptable excipient, The phannaceutically acceptable ent may include s 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 tragacantli, methyl cellulose, liydroxypropylmethyl-cellulose, carboxymethylcellulose sodium, microcrystalline ose 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 ment, the pharmaceutical formulatiOn comprises one or more pharmaceutically acceptable excipients selected from lactose monobydrate, rystalline celiulose, povidone, croscarmellose , or magnesium stearate.

[Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] r Unmarked set by wilksar ation] wilksar None set by wilksar ation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar {0076} 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 ln another embodiment, the solid dosage form is a tablet, In another embodiment, the solid dosage form is a e.

Tablet {(1077} The present disclosure provides a tablet comprising [(4~bydroxy—l~methyl~7~phenox3~ isoquinoiineé‘i«carbonyl)—amino]~acetic acid, a pharmaceutically acceotable excipient and an effective amount of a photostabilizlng agent. in one embodiment, the tablet comprises a tablet core and a coating. {0078} In some embodiments, the photostabilizing agent is d into the tablet or the tablet core.

A tablet or a tablet core is prepared by mixing API with one or more ents such as tillers (diluents), s, disintegrating , 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. [0079} In one ment, the tablet comprises a tablet core and a coating, wherein the tablet core ses [(4nhydroxy- l —methyl—7~phenoxy—isoquinoline~3~earbortyl)uamino]—acetic acid and the pharmaceutically acceptable excipient, and the coating comprises the photostabilizing agent. £0089} Based on the ption and es provided herein and routine practices in the formulations art, one of skill in the art will be able to determine the appropriate amount ofcoating containing the photostabiliaing agent in terms of density and thickness to provide the photostabilization. in one ment, the coating is present in the tablet in an amount that is about 3% to about 8% wiw 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‘liniiting examples of coating include polyvinylalcoholxbased, hydroxyethylcellulose, hydroxypropylmetlryleellulose, [Annotation] r None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] r None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar carboxyrnethylcellulose sodium, polyethylene glycol 4000 and cellulose acetate phthaiate coatings. in one embodiment, the coating is a polyvinyiaicohol—based coating. [0081} in one embodiment, the photostabilizing agent in the tablet comprises titanium dioxide and at least one additional dye selected from the group consisting ofAllura Red AC, Allora Red, AC aluminum lake, iron oxide red, iron oxide yellow, Sunset Yellow PCP, Sunset Yellow FCF um lake, lndigotine, indigotine aluminum lake, and combinations thereof. in another embodiment, the photostabilizing agent comprises titanium dioxide and Allure Red AC aluminum lake. {0082B 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 tabilizing agent in the coating can be bed as % w/w, percent weight of the photostahilizing agent based on the coating weight. in one embodiment, the coating comprises from about 0.1% to about 50% w/w photostabiiizing agent (based on coating weight). in another embodiment, the coating comprises from about 0.5% to about 40% w/ I photostabilizing agent (based on coating weight). In another embodimenfithe coating comprises from about 2% to about. 35% photostabilizing agent (based on coating weight). [0083} The amount of photostabilizing agent in the coating can also be described as the weight of the tabilizing agent applied per surface area unit of the tablet core (mg/oinz). To determine the amount of photostabilizing agent needed to prevent or reduce photodegradation, the tablet core can be coated with s amounts of coatings and each coating may contain different dyes at different quantities. Photodegradation can be monitored by the ance of photodegradation product, if any, upon light exposure r under lCH condition or sunlight). e 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 um lake, not includingother components ofthe um lake. {0084] in one embodiment, the photostabilizing agent in the coating comprises at least about 0.1 ingl’ent2 titanium dioxide and at least one additional dye selected from the group consisting of: at least about 0.1 trig/em2 Allure Red AC; at least about 0.1 2 Allura Red AC in aluminum lake; at least about 0.004 m2 iron oxide red; at least about 0.009 trig/c1112 iron oxide yellow; at least about 0.01 log/em2 Sunset Yellow FCF; and at least about 0.0i ting/om2 Sunset Yellow FCF in aluminum lake; [Annotation] wilksar None set by r [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by r [Annotation] r MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar n the amount. of photostabilizing agent is based on the surface area of the tablet core, {0085] In another embodiment, the photostabilizing agent in the coating comprises from about 0.1 to about 2 tug/cm2 titanium dioxide and at least one additional dye selected from the group consisting of; from about 0.1 to about 0.4 tug/cm2 Allure Red AC; from about 0.1 to about 0.4 mgr/7cm2 Allure Red AC in aluminum lake; from about 0.004 to about 0.4 m2 iron oxide red; from about 0.009 to about 0.2 h iron oxide yellow; from about 0.01 to 0.03 lug/cm2 Sunset Yellow PCP, and from about 0.0l to 0.03 lug/om2 Sunset Yellow FCF in um lake; wherein the amount. ofpbotostabilizlng agent is based on the surface area ofthe tablet core. {0086} lo yet another embodiment, the photostabilizing agent in the coating comprises, based on. surface area ofthe tablet core, from about 0.1 to about 2 tug/cm2 or from about 0.1 to about 0.4 mgfcm2 titanium dioxide, and from about (M to about 0.4 tog/om2 Allura Red AC or Allura Red AC in alumimsm lake. {0087} Further es of various suitable amounts of photostabilizing agents applied to tablet cores are given in Example 2. [0088} In some embodiments, the tablet core comprises from about l'% to about 90% w/w, from about 5% to about 80% w/w, from about 5% to about 40% w/w, from about I 1% to about 30% w/w, % to about 30% w/w or from about 22% to about 28% w/w droxy-l-methyl—7-phenoxy— lsoquinolineé-carbonyl)~amino}~acetic acid, and a phannaceutically acceptable excipient. [0089} In some embodiments, the tablet core comprises about 1 mg to about 400 mg, or about .20 mg to about 200 mg of [(4-l1ydroxy—l—methyl—7—phenoxy—isoquinoline-3“carbonyl)—amirto}~acetic acid, and a pharmaceutically acceptable excipieot, 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 l 00 mg, about £25 mg, about 150 mg, about l75 mg, about. 200 mg, about 250' mg, about 300 mg, about 350 mg, or about 400 mg of [(4~hydroxy«l~methyl~17~pllenoxyosoqulnoline-S— carbonyl)«aminol—acetic acid, and a pharmaceutically acceptable excipient. In other embodiments, the tablet core comprises about '20 mg, about 50 mg, or about l00 mg of {(4~bydroxy~l—methyl—7— phenoxy—isoquinolinefl-carb0nyl)«amincl—acetic acid, and a pharmaceutical ly acceptable excipient, [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [0090} Suitable exciplents are, for example, fillers such as sugars, including lactose, lactose monohydqate, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacantb, methyl cellulose, hydroxypropylmethyl-cellulose, carboxymethylcellulose sodium, microcrystalline cellulose and/or polyvinylpyrrolidone (PVP or ne). if desired, disintegrating agents may be added, such as the linked nyl pyrrolidone, agar, croscarmellose sodium or alginic acid or a salt thereof such as sodium alginate. Also, g agents such as sodium dodecyl sulfate or lubricants such as magnesium stearate may be included. {8091] in one embodiment, the pharmaceutically acceptable excipient comprises lactose monoliydrate, rystalline cellulose, povidone, croscannellose sodium, and magnesium stearate. {(3092} The present disclosure provides a tablet comprising a tablet core and a coating, wherein the tablet core ses {(4~hydroxy— l amethle—phenoxy—isoquinoline»3-carbonyl)~1mino}~acetic acid and a ceutically 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), [08933 In one embodiment, the tablet core ses from about 22% to about 28% w/w [(4~ hydroxy~ l —methyl~7—pbenoxy~isoquinollnen3~carbonyl)—amino]«acetic acid (based on the weight ofthe tablet. core) and a phannaceutically acceptable excipient. in one ment, the pharmaceutically acceptable excipient comprises e ydrate, 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-l-methyl-7~phenoxy—isoquinoline—Scarbonyl)— aminol-acetic acid. In another embodiment, the tablet core comprises about 20 mg, about 50 mg or about 100 mg {(4—liyclroxy-l—rnetliyln7~pbenoxy—isoqulnoline«3~carbonyl)-amincl-acetic acid. {0094} in one embodiment, the photostabilizing agent comprises titanium e and at least one additional dye selected from the» group consisting of Allure Red AC, Allura Red AC aluminum lake, iron oxide red, iron oxide yellow, Sunset Yellow FCF, Sunset Yellow FCF um lake, ludigotine, lndigotine aluminum lake, and combinations thereof. in another embodiment, the tabilizlng agent comprises um dioxide and Allura Red AC aluminum lake. in yet another embodiment, the coating comprises from about'OJ to about 0.4 mgicm2 titanium dioxide and from about 0.1 to about 0.4 rug/om?“ Allure Red AC in aluminum lake wherein the amount oftitanium dioxide and Allura Red AC in aluminum lake is based, on surface area of the tablet core.

[Annotation] wilksar None set by wilksar [Annotation] r MigrationNone set by wilksar ation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar ed set by wilksar The present disclosure provides a tablet comprising a tablet core and a coating, wherein the tablet core comprises droxy«l~methylphenoxy—isoquinoline-B—carbonyl)‘amino]«acetic acid and a pharmaceuticaliy acceptable excipient, and the coating comprises an effective amount ofa tabilizing agent, n the coating is present in an amount from about 3% to about ”/0 w/w {based on the weight of the tablet core), wherein the tablet core ses about 20 mg, about 50 mg or about 100 mg of [(4~hydroxy~ l —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 nag/cm2 titanium dioxide and from about Oil to about 0.4 nag/cm2 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 {0396} The present disclosure provides a capsule comprising [(4—hydroxy—l~methyl-7~phenoxy~ isoquinoiine—3-carbonyl)«aminoi—acetic acid, a. pharmaceuticaliy 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—l~methyl—7—phenoxy—isoquinoline—3— carbonylyaminolsacetic acid and the pharmaceutically acceptable exeipient, and the capsule shell ses the labilizing agent. {0097} in some embodiments, the capsule fill comprises the photost-abiliaing agent, {{4-hydroxy-i — ~7—phenoxy—isoquincline—3~carhonyl)—ainino]-acetie acid, and the ceutically acceptable exeipient. in these embodiments, the capsule fill is prepared by mixing (blending) the photostabilizing agent with API and excipients, {0098] in some embodiments, the photostabilizing agent in the capsule comprises titanium dioxide and at least one additional dye selected from the group consisting ofAllura Red AC, iron oxide red, iron oxide yellow, and ations thereof. In another ment, the photostabilizing agent comprises iron oxide red andtitanium 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 photostabiiizing agent comprises iron oxide red, iron oxide yellow, and titanium dioxide. In still yet another embodiment, the photostabiiizing agent comprises Allure Red AC, iron oxide , and titanium dioxide. In still yet another embodiment, the photostabilizing agent comprises iron oxide yellow and titanium dioxide.

[Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar ation] r Unmarked set by wilksar ation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [8099} Based on the disclosure herein and routine experimentation, one of skill in the art will readily be able to determine the effective amount ol‘photostabilizing agent needed to prevent or reduce the photodegradation of nd A in the capsule. The amount ofphotostabilizing agent in the capsule shell can be described as % w/w, percent weight of the tabilizing 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 ent 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 ent quantities, and the photodegradation of nd A, if any, can be monitored following light exposure (either under lCH condition or sunlight). Example 3 describes several gelatin films with various (lye compositions and their photostabilization results. [0109} in one embodiment, the capsule shell comprises from about 1% w/w to about 7% w/w, lion: aboutl.8% w/w to about 6% w/w, from about 2% w/w to about 4% w/w, or from about 2% wiw to about 3.5% w/w photostabilizing agent (based on weight of e shell). in another embodiment, the capsule shell comprises from about! .8% w/w- to about 6% w/w photostabilizing agent (based on weight of capsule shell). in another embodiment, the e shell comprises from about 2% w/w to about 3.5% w/w photostabilizing agent (based on weight of capsule shell). {01011 In one embodiment, the e shell is a gelatin shell. in r embodiment, the capsule shell is a hydroxypropylmethylcellulose (HPMC) shell. {0102} in one embodiment, the capsule shell comprises about 2% wlw iron oxide red and about 0.9% w/w titanium dioxide (based on weight of capsule shell); or about 0.3% w/w Allure Red AC, about 1% w/w iron oxide yellow, and about l% w/w um 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 l% w/w titanium dioxide (based on weight of capsule shell); or about We w/w iron oxide red, about l% w/w iron oxide yellow, and about 1% w/w titanium dioxide (based on weight of capsule shell); or about l% w/w Allure, Red AC, about l% w/w iron oxide yellow, and about We 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.(basecl on weight of capsule. shell); or about 2% w/w iron oxide yellow and about 1% w/w titanium. dioxide(baseti on weight of capsule shell). {0103} In some embodiments; the capsule fill comprises droxy—l~methyl—7-phenoxy« isoquinolhie-3~carbonyllnamino]-acetie acid in an amount from about 1% to about 90% w/w, from [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] r Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar about 5% to about 80% w/w, from about 5% to about 40% w/w, from about 8% to about 30% MW, % to about 30% w/w or from about 12% to about 5% w/w (based on the weight ofthe capsule fill); and a phannaceutically acceptable excipien‘t. {0:104} lnsome embodiments, the e 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-l anethyln’Y-phenoxy—isoqu‘inolineu3~carhonyl)-aminoj-acetic acid; and a pharmaceutically able excipient. in other embodiments, the capsule fill comprises about 1 mg, about 5 mg, about 10 mg, about l5 mg, about 30 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about l25 mg, about 150 mg, about 1'75 mg, about 200 mg, 3501111250 mg, about 300 mg, about 350 mg, or about 400 mg of {(4uhydroxy‘l —methyl~7—phenoxy—lsoqulnoline-S~carbonyl)— tunino'j—acetic acid; and a phamaceutically acceptable ent. In other embodiments, the. capsule fill comprises about 20 mg, or about 50 mg of [(4~hydtoxysl«methyl~7~phenoxy~lsoqulnolinc-3* carbotzyl}uaminol~acetie acid; and a. pharmaceutically acceptable excipient. {0105} Suitable excipients are, for example, fillers such as sugars, including. lactose, lactose monohydrate, sucrose, mattnitol, or sorbltol; cellulose preparations such as, for e, maize , wheat , rice starch, potato , gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl—eellulose, carboxymethylcellulose sodium, microcrystalline cellulose and/or nylpyrrolidone (PVP or povidone); If desired, egrating agents may be added, such as the oross~llnked polyvinyl pyrrolidone, agar, croscarmellose sodium or alginic acid or a salt thereof such as sodium alglnate. Also, wetting agents such as sodium dodecyl sulfate or lubricants such as magnesium te may be included. [0106} ln one embodiment, the phamlaceutically acceptable exclpient in the capsule comprises lactose monohyd-rate, mlcrocrystalline cellulose, povidone, oroscarmellose sodium, and magnesium {0107} The t di3closure provides a capsule comprising a capsule fill and a capsule shell, wherein the capsule fill ses from about l2% to about 15% w/w- [(Il—hydroxwl—methyl»7— plmxoxy~isoq1tinoline~3-calrbonyl)-amino]~acetic acid (based on the Weight ofthe capsule fill) and a phannaceut‘ically acceptable exclplent, and wherein the capsule shell comprises an effective amount of a photostabillzing agent. lu one embodiment, the phamlaceutlcally acceptable, excipient ses lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate. In another embodiment, the capsule fill comprises about 20 mg or about 50 mg {Oi-hydra} [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar ation] r Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] r MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar 1~methy1~7—phenoxy—isoquinoline—S—earbonyl)-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). {0108} in one embodiment, the e fill comprises about 20 mg or about 50 mg of {(4~hydroxy~ l~methyl-7~phenoxy~isoquinolice~3-carbonyl)-amino]~acetic acid, and phamraceutically able excipients sing 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 e (based on the weight of the capsule shell). {01991 in one embodiment, the capsule fill comprises about 20 mg or about 50 mg of [(4Ihydroxy« yi~7-phenoxy-isoquinoline«3-carbonyl)—amino}acetic acid, and phamiaeeutically acceptable ents 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 Allure Red AC, about l% w/w iron oxide yellow, and about 1% w/w titanium dioxide (based on the weight of the capsule shell). {01 10} In one embodiment, the capsule fill comprises about 20 mg or about 50* mg of {(4—hydroxy- l~methyl-7—phenoxy-isoquinclinc—3ncarbonylyaminojacetic acid, and pharmaceutically acceptable excipients comprising lactose mouohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate; and wherein the capsule shell is a n 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). {ill 1 ii In one embodiment, the capsule-fill Ses about 20 mg or about 5.0 mg of [(4—l1yclroxy— l—methyl-'7'—phenoxydsoquincliniccarbonyl}~amioo}—acetic acid, and pharmaceutically acceptable excipients comprising lactose monohydxate, microcrystalline cellulose, povidoue, croscarmeliose sodium, and magnesium stearate; and n the capsule shell is a gelatin shell comprising about We w/w iron oxide red, about 1% w/w iron oxide yellow, and about We w/w titanium e (based on the weight of the capsule shell). [01123 in one ment; the capsule fill comprises about 20 mg or about 50 mg of {(4-hydroxy« 1-me‘lhyi—7—phenoxy-isoquinolinc—3~carbonyl)--amiuo]Acetic acid, and pharmaceuticaliy acceptable excipients comprising lactose mouohydrate, microcrystailine cellulose; povidone, croscarmellose sodium, and magnesium te; and wherein the capsule shell is a gelatin shell comprising about 1% [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar ation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar ed set by r w/w Allure Red AC, about 1% w/w iron oxide yellow, and about 1% w/w titanium dioxide (based on the weight of the capsule shell). [0113} in one embodiment, the capsule till comprises about 20 mg or about 50 mg of {(4-hyd'roxy~ l—methyl—7~phenoxy~isoquinoline—3~carbonyl)~amino}uacetic acid, anti pharmaceutically acceptable excipients comprising lactose monohydratc, microcrystalline cellulose, povidone, croscnrmellosc soditnn, and magnesium stearate; and wherein the capsule shell is a n shell comprising about 2% w/w iron oxide red, and about l% w/w um e (based on the weight of the e shell). 10114} in one embodiment, the capsule fill comprises about 20 mg or about 50' mg of {(4—hyclroxy— l~methyl—7~phenoxy-isoquinoiine—‘3-carbonyl)—aminol~acetic acid, and phmnaceutically acceptable exeipients sing lactose monohydrate, microorystalline 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 l% w/w titanium dioxide (based on the weight of the capsule shell).

Routes of Administration {91151 Suitable routes of administration may, for example, include oral, , transmucosal, nasal, or intestinal administration and parenteral delivery, including uscular, subcutaneous, intramcduilary ions, 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, phannaccuticai formulation can be red via injection or in a targeted drug deliveiy system, such as a depot or sustained reiease ation. in one ment, the route of administration. is oral. When the pharmaceutical formulation is administered orally, it may be administered as a tablet or a capsule. {0116} The pharmaceutical formulations of the present disclosure may be manufactured by any of the methods well—knowu in the art, such as by conventional mixing, dissolving, granulating, drag‘ee- making, levigating, emulsi ring, 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. {9117} l’roper ation is dependent upon the route of administration chosen. For injection, for e, the composition may be formulated in aqueous solutions, preferably in physiologically [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by r [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar compatible buffers such as llanlcs‘ on, 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 thezart, in one embodiment ofthe present disclosure, the pharmaceutical formulations are intended for oral stration. For oral stration, it can be formulated readily by combining Compound A with pliamiaceutically acceptable excipients well known in the art. Such excipients enable Compound A to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, sions and the like, for oral ingestion by a subject. The pharmaceutical formulation may also be formulated into rectal compositions such as suppositories or retention , cg, containing conventional suppository bases such as cocoa butter or other glycerides. {0118} Pharmaceutical preparations for oral use can be obtained using solid excipients, optionally grinding a resulting mixture, and processing the mixture ules, after adding suitable auxiliaries, if desired, to obtain tablets or tablet cores. Suitable excipients are well known in the art and are described ere herein. {0119] Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin, l-ll’MC, and other suitable materials, as well as soft, sealed es 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 es, and/or ants such as talc. or magnesium stearate and, optionally, stabilizers. In soft es, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid n, or liquid polyethylene glycols. In addition, stabilizers may be added. {01291 The pharmaceutical formulations may also be formulated asa depot preparation. Such long acting formulations may be stered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the pharmaceutical formulations may be formulated with suitable ric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as gly soluble derivatives, for example, as a sparingly soluble salt. {0121} For any composition used in the various treatments embodied herein, an effective close (or eutically effective dose) can be estimated initially using a variety of ques 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 K35” as determined in cell culture. Dosage ranges [Annotation] r None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] r Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar appropriate for human subjects can be determined, for example, using data obtained from cell culture assays and nonshuman animal studies. in one embodiment, the dosage may be from 0.05. rag/kg to about 700 rag/kg. Typically, the dosage may be from about 0.05 mgikg to about 500 mg/kg; from about 0.1 rug/kg to about 250 sing/kg; from about 0.2 tug/kg to about 100 tog/kg; from about 0.3 mg/kg to about it) tug/kg; from about 0.5 rag/kg to about 5 mg/kg; or from about 1 mg/kg to about 2 rug/kg. For example, the dosage may be about 0.5 rag/kg; about 0.7 org/kg; 1.0 rug/kg; about 1.2 mg/kg; about 1.5 trig/kg; about 2.0 nag/kg; about 2.5 rug/kg; about 3.0 trig/kg; about 3.5 mgz’kg; about 4.0 mg/kg; about 4.5 rug/kg; or about 5.9 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. lly, the dosages is administered 2 or 3 times a week. [0122} A therapeutically effective dose of a compound refers to that amount of the compound that results in ameiioratiou of symptoms or a prolongation of survival in a t. Toxicity and therapeutic efficacy of such molecuies can be determined by standard pharmaceutical procedures in cell ouitures or experimental animals, e.g., by determining the L050 {the close lethal to 50% ofthe population.) and the E950 (the dose eutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can he expressed as the ratio LDgo/EDSO.

Compounds that exhibit high therapeutic indiees are preferred.

Dosages preferably fall within a range of ating concentrations that inciudes the E1350 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. [0124} Dosage amount and interval may be adjusted individuaiiy to provide plasma levels of the active moiety that are ient to te a desired parameter, e.g., endogenous -DpOiCt‘lil plasma levels, Le. minimal effective tration (MEG). The MEC will vary for each compound but can be estimated from, for example, in vitro data. In cases of local stration 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 nous erythropoietin, may he achieved by i) administering a loading dose followed by a nance dose, 2) administering an induction dose to rapidly achieve the desired parameter, e.g., opoietin , within a target range, followed by a lower maintenance dose to maintain, e.g., hematocrit, within a desired target range, or 3) ed intermittent dosing.

[Annotation] wilksar None set by wilksar ation] wilksar MigrationNone set by wilksar [Annotation] r ed set by wilksar [Annotation] r None set by wilksar [Annotation] wilksar MigrationNone set by r [Annotation] wilksar Unmarked set by wilksar [9 {25} The amount of compound or composition administered will, of course, be dependent on a variety of factors, inciuding the sex, age, and weight ofthe subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician. {0126] The t compositions may, if d, 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 metai or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Pharmaceutical formuiations ofthe disciosure formulated in a compatibie pharmaceutical excipient may aiso be prepared, placed in an appropriate container, and iabcled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of conditions, ers, or diseases in which anemia is a major tion.

Methods {9127} The present disclosure provides a method of ting (preventing and/or reducing) the pilotodegradation of {(4~hydrox_y«1~methyi-7—phenoxy~isoquinoiine~3~carbonyl)—amino]-acetic acid (Compound A). in one embodiment, the method comprises forrnuialing {(4~hydroxy—i~methyl-7— phenoxy—isoqninoiine-S-carbonyl)-amino]-acetic acid with an effective amount ofa photostahilizing agent. An effective amount of photostabilizing agent is the amount sufficient to innit the amount of photodegradation product of Compound A that is produced to a level that is iess than about 0.2% w/w Compound A (or 2000 ppm), under lCH conditions. In one embodiment, the photostabiiizing agent comprises titanium dioxide. in one embodiment, the photostahiiizing agent comprises a dye. in some embodiments, the method comprises formulating [(4—hydroxy-l i—7—phenoxy-isoquinoiine-3~ carbonyl)—amino}«acetic acid with titanium dioxide and at toast one additional dye. in a further embodiment,, the photostabiiizing agent blocks light at a wavelength range of between about 220 and about 550 nm. In other ments, the dye is selected from the group consisting of a black dye, a biue dye, a green dye, a red dye, an orange dye, a yellow dye, and combinations thereof. in another embodiment, the dye is seiectecl from the group consisting of a red dye, an orange dye, a yellow dye, and combinations thereof. The present ion further provides a method of inhibiting (preventing and/or reducing) the photodegradation of [(4-hydroxy—i~methylphenoxy—isoqtnnoline--3—carhony})— ~acetic acid (Cornponnd A), the method comprising formulating [(4nhydroxy~1~methyl-7— phenoxy‘isoquinolines~carbonyi)exiting-acetic acid with an effective amount ofa photostabilizing [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar ation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar agent, and a pharmaceutically acceptable excipieni. Various formulations comprising photostabllizing agents have been described . {(33281 Compound A can be formulated with the photostabilizing agent in any conventional manner, for example, by mixing or blending nd 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 sing nd A with a coating comprising the photostabilizing agent, or by enclosing a capsule till comprising Compound A within a. capsule shell comprising the photostabilizing agent. {0129} in other embodiments, the method of inhibiting the degradation of Compound A can be achieved with tabilizing 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 d to, opaque containers or wrappings such as, a brown bottle, a blackulined , an amber vial, an opaque blister pack, a blister packmadc from a blister film Containing a tabilizlng agent, and a ined packaging. {0130} 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. {0131} “fire inedicaments or itions can be used to modulate the stability and/or activity of l-llF, and thereby activate HlF‘regulated gene expression. In one aspect, the medicaments or compositions can be used to inhibitor reduce the activity ofa HIF hydroxylase enzyme, particularly 2! PK? ptolyl hydroxylase enzyme, for example, EGLNl, EGLNE, LN3 (also known as PHDZ", PHD] and PHD3, respectively), bed by Taylor (2001,Gene 1375125432), and characterized by Aravind and Koonin (2001, Genome Biol 22RESEARCHOOO7), Epstein et al. (2001, Cell 107:43—54), and Bruick and ht (2001, Science 294: l337-1340). {313% The pharmaceutical formulations described herein can be used in methods to treat, modem, or delay progression or onset of conditions ated with HIF including, but not limited to, anemic, ischemic, and hypoxic conditions. in various embodiments, the pharmaceutical ation is administered immediately following a condition producing acute ischemia, e. g., myocardial infarction, pulmonary embolism, intestinal infarction, ischemic , and renal ischemic—rcperliision [Annotation] wilksar None set by wilksar [Annotation] wilksar ionNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar ation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar injury, in r embodiment, phannaceutical formulation is administered to a patient diagnosed with a condition associated with the development of chronic ischemia, cg. , cardiac cirrhosis, r degeneration, pulmonary embolism, acute respiratow failure, neonatal respiratory distress syndrome, and congestive heart e. in yet another embodiment, pharmaceutical formulation is administered immediately after a trauma or injury. in other ments, pharmaceutical formulation can be administered to a subject based on predisposing conditions, eg. , hypertension, diabetes, occlusive arterial disease, chronic venous insufficiency, Raynaud’s e, chronic skin ulcers, cirrhosis, tive heart failure, and systemic sclerosis. in still other embodiments, pharmaceutical formulation may be administered to pretreat a t to decrease or t the development of tissue damage associated with ischemia or hypoxia. In other ments, 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 (cg, ulcerative s) and Crohn’s disease. [0133} The ceutical formulations and itions 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 , to increase blood hemoglobin levels, and/or to increase heinatocrit, in a t with chronic kidney disease or end stage renal disorder. in one aspect, the pharmaceutical ations 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 ofchronic disease, {@134} 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, sing 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 s for or that develop in parallel with or as a result of diabetes. {01355 The pharmaceutical ation can also be used to increase endogenous erythropoietin (EPQ). The pharmaceutical formulation can be administered to prevent, preheat, or treat EPO- associated conditions, including, cg, conditions associated with anemia and neurological disorders.

Conditions associated with anemia include ers such as acute or chronic kidney disease, diabetes, cancer, ulcers, infection with virus, cg, HIV, bacteria, or parasites; inflammation, etc. Anemia ation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar ation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar conditions can fiuther include those associated with procedures or treatments including, cg. , radiation therapy, chemotherapy, dialysis, and surgery. ers associated with anemia additionally include abnormal hemoglobin and/or erythrocytes, such as found in disorders such as microcytic anemia, hypochromic anemia, aplastic anemia, etc. [0136} in one aspect, the pharmaceutical formulations and compositions can be used in a method for inducing enhanced or complete erythropoiesis in a subject.

The disclosure is also ed to use ofa pharmaceutical formulation to treat, pretreat, or delay onset of a ion associated with a disorder selected from the group consisting of anemic ers; neurological disorders and/or injuries including cases of stroke, trauma, epilepsy, and neurodegenerative disease; cardiac isehemia including, but not limited to, myocardial infarction and congestive heart failure; liver ischemia ing, but not limited to, cardiac cirrhosis; renal isc‘nemia ing, but not limited to, acute kidney failure and chronic kidney failure; peripheral vascular ers, ulcers, burns, and chronic wounds; pulmonary embolism; and ischemicareperfusion injury. in one aspect the formulations and compositions are useful in a method for treating multiple sclerosis and/or increasing neurogenesis. [913?” in a further aspect, the formulations and compositions can be used in a method for ng blood re 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. {0139} in another embodiment, the t invention provides use for the formulations and compositions in a method for improving kidney function in a t having or at risk for having impaired kidney function, the method comprising stering to the subject an agent that inhibits. hypoxia inducible factor (RIF) ylase activity. [8140} in another aspect, the formulations and compositions can be used in a method for regulation ofiron processing and treatment/prevention of conditions associated with ncies 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 molest. {0141} In r , 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 tile [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar ation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar circulating level of low density lipoprotein cholesterol and/or very low density lipoproiein cholesterol, and/or increasing the ratio of high density lipoprotein cholesterol/low y protein cholesterol. {0142} Methods of using HIP prolyl hydroxyiase inhibitors, and, in particular, Compound A, to treat s conditions and disorders have been bed in numerous publications including, U.S. Patent Application Publication Nos. BOOTS/0176317, 2003/0153503, [2004/0204356, ROM/0235082, EGGS/0020487, 200710042937, BOW/000.4627, zoos/0276477, 2007/0293575,‘ 2012/Ol49712, 2007/0259960, EON/0292433, 2011/0039878, 20l 885, 2010/0l4473’7, 201 ”0039879, and 201 1/0263642; PCT Foblication No. \V02012/097329, W020121097331, and WO2Gl3/‘O70903; International Patent Application No. PCT/US20l 3.102985 1 {9143] 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 hydroxylsse including, but not limited to, the group consisting of EGLNI, EGLNZ, and EGLN3 (also known as PHDZ, PHD} and PHD3, respectively), described by Taylor Gene 275:125—132), and characterized by Aravind and Koonin (200i, Genome Biol 2:RESBARCI~10007), Epstein et a1. (2001, Cell —54), and r and McKnight (2001, Science 294:1337~l 340). The method comprises contacting the enzyme with Compound A. in some embodiments, the HIP hydroxylase enzyme is an asparaginyl hydroxylase or a prolyl ylase. in other embodiments, the HIP hydroxylase enzyme is a factor inhibiting HlF, human EGLNl , EGLNZ, or EGLN3. {0144} While this disclosure has been described in conjunction with specific embodiments and examples, it will be apparent to a person ofordinary skill in the art, having regard to that skill and this sure, that equivalents ofthe specifically disclosed materials and methods will also be applicable to this disclosure; and such lents are intended to be included within the following claims. e 1. Solid State Sunlight Exposure of Compound A {0145} imately 500 mg ofCompound A dry powder was placed in a lugallon hylene 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 ali the powder and not just the top layer was exposed to sunlight. A control sample of Compound A powder was stored in an ember vial in the dark for the same amount oftime for comparison purposes. After two months, visuai inspection of [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar ionNone set by wilksar [Annotation] wilksar Unmarked set by wilksar the two samples indicated that the light~exposed sample had become i’re, 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 ition. The HPLC method used a. e phase Zorbax Eclipse , 3.5 um, 4.6 \ 150mm column. The mobile phase was comprised of water and acetoniirile mixtures acidified with irifluoroacetic acid. Gradient elation with increasing irrlle provided cm‘omatogranis oflhe control sample ofCompound A (FK}. i, before light exposure) and the lightexposed sample ofCompound A ( alien“ light exposure) with UV detection at 230 nm. The HPLC ofthe light-exposed sample shows the appearance of a new peak, designated as “Photodegradation Product” in FlG.l. {0146} Before re to sunlight, the Compound A powder had a purity value of 99.1 % as ed by reverse phase HPLC and no single impurity was present at a. level above 0.2% w/w (2000 ppm} Afier exposure to sunlight, the Compound A powder had a slightly lower purity value of 98.4%. Alter 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 ofCompound A decreased on exposure to sunlight and the new molecule appeared suggests that a fraction of nd A is converting to the new molecule, a photodegradation product.

Example 2. Photcstabiiizing Coating of Tablet {0147} it was found that tablets comprising {(4—hydroxy- l amethylfluphenoxy-isoquinoline-S— carbonyl)~amino}»acetic acid photodegrade upon exposure to light. To reduce the photodegradation of nd A in the tablets, various gs were tested for their photostahilizing properties. [0148} Pink/Peach coating formulas tested, included a coating comprising Formula 1: iron oxide red, iron oxide yellow and titanium dioxide /Peach #1”); Formula 2: Sunset Yellow FCF, iron oxide red and um dioxide (“Pink/"Peach #2"); or Formula 3: iron oxide red, iron oxide yellow and titanium dioxide (“Pink/Peach #3”). {6149} The red coating formulas tested included a coating comprising Formula 4: Allura Red AC and lndigotine um lakes, and titanium dioxide (“Allura Red AC/Iiidigotine”); Formula 5: Allure Red AC aluminum lake and, titanium dioxide (“Allura Red AC”); or Formula 6: Iron oxide red and titanium dioxide (“Red iron Oxide”).

[Annotation] wilksar None set by r [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar {0150} Tablets comprising either 20 mg or 100 mg of [(4vhydrexy-l~methyl~7—phenoxy- isoquinolinc-3«earbonyD-amino]~acetic acid were coated in an evenly distributed layer with different amounts ofphotostabilizing agent per tablet surface area (mg/cmz) in a coating yam with d lighting. Table 1 lists examples oftablet coatings at s levels using different coating formulas.

The 3%, 4%, 4.5% or 7.5% g level is the percent-age of the weight 0ftll€ coating material over the weight of the tablet core being coated Table i: Examples of tabilizing Agents per Tablet Surface Area Present in s Coated at Different Coating Levels 28 mg sfrengtll tablet with 3% target coating level Formula Formula Formula I Formula ' la 4'153.......L-.62_.l TeialAllura Red AC (m cmz) 9£000 l“_______ 'rosgljflgggggge {m cm?) 5 0.000 : 0;p_Q§_>_____ “Zeta! Sunset Yellow FCF (“1M QQQQ___________________ ______ Red iron oxide mg/cmz) Tetal Allure Recl AC (mgi’cmz) Total .lndi gotineiggl/cnlz) ______ Total Sunset Yellow FCF (mg/9mg) Red iron oxide (mg/emz) Formula Formula 5 Formula Total Allura Red AC (mgang} 1 0.000 0.341 Total lndi otine (m 0mg} .. ___________ ;§_g§g_lmgioxide(m cmz) . , 2.652__ | 0.316 "me..— ation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar 100 mg th tablet with 3% target coatin level .........f._ 1 ‘ Formula Fommla Formula Formula Formula E Formula 1 3d 391-..--- 46 so i 6:! ' WWW...............

I‘otai“Allgggggd AC (m Man 0000. 0.000 5 0.000 _____ 0:339______1t29153i_____ 0000 __“Eotal Indigotine (11131::ng L__________. - 0.000 0.000 - x . s . 0.000 1'........ “MW"...

Formula Formula Formula Formula Formula 1 Formula 22 3e 4e 6e _mwmmm______3pm ___________________13'}3.1—1 T0331Allura Red AC (mg/03112) 0.000 0.000 0.000 0.320 E _Igggllgdigotine ) "0000““ 0.000 I 0.000 0.001 Total Sunset Yellow FCF (m cm2) E 0.000 0.02} 0.000 0.000 Rediron mg/cng__)_~ i 0.018 0.006 0.000 _________ _j_____g.913 _E Yellowimn mgiglgggig/cmz) I 0100 0:000_____ l I 0023 0.000 Formula 5 Formula lTotalAlluraRedACgmg/cmz) .

...... Total Indi otine (m .cmz) oom ___._...A_.__... _’i‘otal Sunset Yellow FCF m /cm2 Red'Iron oxide (on * cm2 v E 0355 ..... OOQLLugpoo . '. ». ___;ggiggmjw 0.000 f 0009 ......................... {0151} The coated tablets were exposed to light (ICE-i Option 2}, and tested for photodegradation by ing the amount of photodegradation product that was present by using m‘verse phase HE’LC.

Dark ls were d in aluminum foil. The reverse phase HPLC method used to quantify photodegradation t had an upper quantitation limit of0.25% 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 iower sensitivity, was used. Tables 2 anti 3 Show mean values (3:10) of [Annotation] r None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar ionNone set by wilksar [Annotation] wilksar Unmarked set by wilksar phoodegradation product (in ppm relative to Compound A) for eaci1 red-coated tablet batch tasted “ND” refers to not determined. ‘NA' refers to not applicable.

Tabie 2: Photodegradation of 29 mg Strength Tablet with Red Coatings Coating a Coating Light T Photodegmdation i’roduct Levei Exposure Mean Value Allura Red AC/ F0111111121 4a 1C1! Option 2 5 1645 a 5a 10H Option 2 1836 Alinra Red AC ICH Option7 Fmmuia 6a 3% H Red Iron Oxide Dark Contxol Formuia6b ICH OptionZ Photodegradatien Product . _~ Mean Vaiue Ailura Red AC/: indigotine Formuia 5d Allan-a Red AC , FormuaSe 4% -ICHOpfionERedIronOxzde * , -- ~ ICH Option 2 [CH Option 2 {0152} These resuits are depicied graphically in (20 mg strength tabiet) and 2B (100 strength tabiet). {0153] Photodegradation rcsuits for tablets coated with pink/peach formulas at {316394) or 4% g lave} (based on the weight of the tabiet core), afier exposure to ICH Option 2 conditions are shown. in and Table 4 for the 20 mg strength tablets, anti in FIG. BB and Table 5 for thc 100 mg strength tabiets.

[Annotation] wilksar None set by wilksar ation] wilksar MigrationNone set by r [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] r MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar Table 4: E’Emmdegradation of 20 mg Strength Tablet with Pink/Peach Coatings ______ g Formula Coating Light I egraé-a-t-log—Pmduct Level Exposure j ' Mean wlw, 7 ‘ ICH OtionZ >200 Formula la 39/° -: Pink/Peach #l 98mm Formula lb 4% : ICE Option 2 ”mum 23 -_2 *0 {CH 0 ion 2 Pink/Peach #2 Formulle -- ICH Otion 2 32500 Pmk/Peach #9 ‘" lsoxmula 3b — ICH)pt10n 2‘ , . . 32500 Table 5: Photodegradation of 100 mg Strength Tablet with Pink/Peach Coatings _---------- 3 Coating Coating wLiglJ Photodegra<§ail¢3§§§odact Formula Level re Mean w’iw V . ‘= m l , Formula 1d 0 : {CH 0 tin 1 2 each#l - ‘ p‘ I 88? Formula 16 — [CH Quonz_ V m . , Fommla 2d ; ECH Option 2 l 173 Pmk/Peacn #2 » g - ,V .. _Formula. 2e - ma Otion 2 ~ “0 ICH O t' 2 V lozmula 3d p 10?! 1885 Pimic/Peach #3 ' a3e -' lCHOtionZ 113's Example 3. Phatostabilizing Gelatin Capsule {0154i Compound A in gelatin capsules also ts photodegradation upon, light exposures.

Gelatin film coatings containing various dye combinations were tested for their photostablllzing properties. {0155} n, capsules comprising {(4vhydroxy-1 “mothyl-Wphenoxy-isoquinolinoS-carbonyl} animal—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-l~methyl~7gphenoxy—isoquinoline-S«carbonyl)~ aminol-acetic acid by measuring the amount ofphot’odegradation product using reverse phase H9113 described in Example 1. Results represent the mean value ofphotodegradatlon product measured in capsules, [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar [Annotation] wilksar None set by wilksar [Annotation] wilksar MigrationNone set by wilksar [Annotation] wilksar Unmarked set by wilksar {9:56} The composition of the hard gelatin films tested is shown in Table 6 below.

Table 6: Gelatin Fiims Ingredient - ghased on weight ofeagsuie she“; Orange #1 Yeliow iron oxide 1% .....

Allura Red 0.3% Titanium dioxide Yellow iron oxxde Red ‘ron oxide um dioxide Red iron oxxd‘e Titanum dioxide Yeilow iron oxide Titanium doxde Orange #4 Yiiow iron oxide Allura Red AC fltan‘um dioxide Blue Indieotine Titanium dioxide Red #2 Red iron oxide Titanium dioxide 50157} As shown in Table 7 and the orange dyes offered the best photostabilization of nd A in the hard gelatin capsules.

Table '7: Photodegmdation of Hard Gelatin es Containing Compound A Gelatin Fing Orange #1 1003525934

Claims (26)

1. A tablet comprising a tablet core and a coating, wherein the tablet core comprises [(4- hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid and a pharmaceutically able excipient, and the coating comprises an effective amount of a photostabilizing agent, and wherein the photostabilizing agent comprises at least about 0.1 mg/cm2 titanium dioxide and at least one additional dye or pigment selected from the group consisting of: at least about 0.1 mg/cm2 Allura Red AC; at least about 0.1 mg/cm2 Allura Red AC in aluminum lake; at least about 0.004 mg/cm2 iron oxide red; at least about 0.009 mg/cm2 iron oxide yellow; at least about 0.01 mg/cm2 Sunset Yellow FCF; and at least about 0.01 mg/cm2 Sunset Yellow FCF in aluminum lake; wherein the amount of photostabilizing agent is based on surface area of the tablet core.

2. The tablet of claim 1, wherein the photostabilizing agent comprises, from about 0.1 to about 2 mg/cm2 titanium dioxide and at least one additional dye or t selected from the group consisting from about 0.1 to about 0.4 mg/cm2 Allura Red AC; from about 0.1 to about 0.4 mg/cm2 Allura Red AC in aluminum lake; from about 0.004 to about 0.4 mg/cm2 iron oxide red; from about 0.009 to about 0.2 mg/cm2 iron oxide yellow; from about 0.01 to 0.03 mg/cm2 Sunset Yellow FCF; and from about 0.01 to 0.03 mg/cm2 Sunset Yellow FCF in aluminum lake; wherein the amount of photostabilizing agent is based on e area of the tablet core.

3. The tablet of claim 1 or 2, wherein the at least one additional dye or t is Allura Red

4. The tablet of claim 1 or 2, wherein the at least one additional dye or pigment is Allura Red AC in aluminum lake.

5. The tablet of claim 1 or 2, wherein the at least one additional dye or pigment is iron oxide red.

6. The tablet of claim 1 or 2, wherein the at least one additional dye or pigment is iron oxide yellow. 1003525934

7. The tablet of claim 1 or 2, wherein the at least one onal dye or pigment is Sunset Yellow FCF.

8. The tablet of claim 1 or 2, wherein the at least one additional dye or pigment is Sunset Yellow FCF in aluminum lake.

9. The tablet of claim 1, wherein the coating ses from about 0.1 to about 0.4 mg/cm2 titanium dioxide and from about 0.1 to about 0.4 mg/cm2 Allura Red AC in aluminum lake wherein the amount of titanium dioxide and Allura Red AC in um lake is based on surface area of the tablet core.

10. The tablet of any one of claims 1-9, wherein the coating is present in an amount from about 3% to about 8% w/w based on the weight of the tablet core.

11. The tablet of any one of claims 1-10, wherein the tablet core comprises from about 22% to about 28% w/w [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid based on the weight of the tablet core and a pharmaceutically acceptable ent.

12. The tablet of claim 11, wherein the pharmaceutically able excipient comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate.

13. The tablet of any one of claims 1-12, n the tablet core comprises from about 20 mg to about 200 mg [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid.

14. The tablet of claim 13, wherein the tablet core comprises about 20 mg, about 50 mg or about 100 mg [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid.

15. A capsule comprising a capsule fill and a e shell, wherein the capsule fill comprises [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient, and the capsule shell comprises a photostabilizing agent, wherein the photostabilizing agent comprises about 2% w/w iron oxide red and about 0.9% w/w titanium dioxide based on the weight of the capsule shell.

16. A capsule comprising a capsule fill and a capsule shell, wherein the capsule fill comprises [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient, and the capsule shell comprises a photostabilizing agent, wherein the photostabilizing agent comprises 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.

17. A capsule comprising a capsule fill and a capsule shell, wherein the capsule fill comprises [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient, and the capsule shell comprises a photostabilizing agent, wherein the tabilizing agent comprises about 0.7% w/w iron oxide red, about 0.3% w/w Allura Red AC, 1003525934 about 1% w/w iron oxide yellow, and about 1% w/w titanium dioxide based on the weight of the capsule shell.

18. A capsule comprising a capsule fill and a capsule shell, wherein the capsule fill comprises [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient, and the capsule shell comprises a tabilizing agent, wherein the photostabilizing agent ses 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.

19. A e comprising a capsule fill and a capsule shell, wherein the capsule fill comprises [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient, and the e shell comprises 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.

20. A capsule comprising a capsule fill and a e shell, wherein the capsule fill comprises [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient, and the capsule shell comprises about 2% w/w iron oxide red, and about 1% w/w titanium dioxide based on the weight of the capsule shell.

21. A capsule comprising a e fill and a capsule shell, wherein the capsule fill comprises [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid and a pharmaceutically acceptable excipient, and the capsule shell comprises about 2% w/w iron oxide , and about 1% w/w titanium dioxide based on the weight of the capsule shell.

22. The capsule of any one of claims 15-21, wherein the capsule shell is a gelatin shell.

23. The capsule of any one of claims 15-22, wherein the capsule fill comprises from about 12% to about 15% w/w [(4-hydroxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid based on the weight of the capsule fill and a pharmaceutically acceptable excipient.

24. The capsule of claim 23, wherein the pharmaceutically acceptable excipient comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate.

25. The capsule of claim any one of claims 15-24, wherein the e fill comprises about 20 mg or about 50 mg droxymethylphenoxy-isoquinolinecarbonyl)-amino]-acetic acid.

26. The tablet of claim 1 or the capsule of any one of claims 15-21 as substantially bed herein with reference to and as illustrated by the accompanying drawings.