WO2015174948A1 - Formulations comprenant des composés de lipoyle - Google Patents

Formulations comprenant des composés de lipoyle Download PDF

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Publication number
WO2015174948A1
WO2015174948A1 PCT/US2014/000090 US2014000090W WO2015174948A1 WO 2015174948 A1 WO2015174948 A1 WO 2015174948A1 US 2014000090 W US2014000090 W US 2014000090W WO 2015174948 A1 WO2015174948 A1 WO 2015174948A1
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formulation
alkyl
compound
structural formula
pharmaceutical formulation
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PCT/US2014/000090
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English (en)
Inventor
Steven A. Kates
Ralph Casale
Alan S. Lader
Alexander B. Baguisi
Reinier BEEUKWES
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Ischemix, LLC
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Priority to PCT/US2014/000090 priority Critical patent/WO2015174948A1/fr
Publication of WO2015174948A1 publication Critical patent/WO2015174948A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds

Definitions

  • Ischemic injuries are injuries resulting from restricted blood supply to an organ or tissue. Paradoxically, restoration of blood flow to affected tissues and organs following an ischemic episode can cause a secondary injury, ischemia-reperfusion injury. Ischemia- reperfusion injury often exacerbates the original ischemic injury, adding to the extent of organ or tissue damage.
  • lipoyl compounds have a propensity to form impurities such as polymers upon exposure to light, a reaction proposed to proceed by photolytic opening of the dithiolane ring resulting in a diradical, followed by propagation through intermolecular disulfide bond formation (see Id. at 506).
  • Potential degradation, including polymerization- induced degradation, of lipoyl compounds is, therefore, of concern in the development and formulation of therapeutic agents comprising lipoyl-containing compounds.
  • Efforts to produce lipoyl compounds free of impurities, including contaminating polymeric impurities have focused on crystallization and salt formation, neither of which are relevant to
  • This invention relates to aqueous pharmaceutical formulations comprising monomeric lipoyl compounds (e.g., monomeric lipoyl compounds substantially free of impurities).
  • the formulations comprise a lipoyl compound that is substituted with at least one acidic substituent; and an inorganic base in an amount sufficient to deprotonate each acidic substituent in the lipoyl compound.
  • the formulations have a pH of from about 6.5 to about 8.0 and a tonicity of from about 250 mOsm to about 350 mOsm.
  • One embodiment of the invention relates to an aqueous pharmaceutical formulation, comprising a com ound represented by Structural Formula I:
  • the formulation further comprises an inorganic base in an amount sufficient to deprotonate each acidic substituent in the compound of Structural Formula I, and has a pH of from about 6.5 to about 8.0 and a tonicity of from about 250 mOsm to about 350 mOsm.
  • Another embodiment of the invention relates to an aqueous pharmaceutical formulation, comprising (i) from about 9 mg/mL to about 30 mg/mL of a compound represented by Structural Formula Ila:
  • the formulation has a pH of from about 6.8 to about 7.6 and a tonicity of from about 260 mOsm to about 320 mOsm.
  • the compound of Structural Formula Ila (a-N- [(R)-l,2-diothiolane-3-pentanoyl]-L-glutamyl-L-alanine) is also referred to herein as (R)Lip- EA-OH.
  • Yet another embodiment of the invention relates to a process for preparing an aqueous pharmaceutical formulation.
  • the process comprises providing a compound represented by Structural Formula I and providing an aqueous solution comprising an inorganic base in an amount sufficient to deprotonate each acidic substituent in the compound of Structural Formula I.
  • the volume of the aqueous solution is equal to or greater than about 75% of the volume of the formulation.
  • the compound of Structural Formula I is added to the aqueous solution, thereby forming a pharmaceutical solution, and the pharmaceutical solution is diluted to the volume of the formulation with a diluent to thereby prepare the aqueous pharmaceutical formulation.
  • a process for preparing an aqueous pharmaceutical formulation having a pH of from about 6.5 to about 8.0 and a tonicity of from about 250 mOsm to about 350 mOsm comprises providing an aqueous solution comprising an amount of sodium hydroxide sufficient to form a formulation comprising from about 25 mg/n L to about 200 mg/mL sodium hydroxide, wherein the volume of the aqueous solution is equal to or greater than about 75% of the volume of the formulation.
  • a compound represented by Structural Formula Ila is added to the aqueous solution in an amount sufficient to form a formulation comprising from about 5 mg/mL to about 50 mg/mL of the compound of Structural Formula Ila, thereby forming a pharmaceutical solution.
  • the pharmaceutical solution is diluted to the volume of the formulation with a diluent, to prepare the aqueous pharmaceutical formulation having a pH of from about 6.5 to about 8.0 and a tonicity of from about 250 mOsm to about 350 mOsm.
  • aqueous pharmaceutical formulations made according to the processes for preparing aqueous pharmaceutical formulations described herein.
  • the formulations described herein inhibit or eliminate the formation of undesired impurities, including polymeric impurities resulting from the polymerization of a monomeric lipoyl compound in the formulation.
  • the formulations are stable for at least several months and, therefore, provide a means for delivering pure or substantially pure monomeric lipoyl compounds to a patient in an aqueous pharmaceutical formulation suitable for intravenous administration.
  • the formulations can be administered safely to patients to treat or prevent ischemic and ischemia-reperfusion injuries.
  • FIG. 1 is a copy of an HPLC chromatogram of the 30 mg/mL (R)Lip-EA-OH formulation resulting from the initial formulation protocol described in Example 2.
  • (R)Lip- EA-OH was formulated by neutralizing solid (R)Lip-EA-OH with aqueous 1 N sodium bicarbonate and then diluting to volume with saline and water for injection.
  • the chromatogram is enlarged to emphasize the products eluting in the baseline.
  • the peak eluting at 12 minutes corresponds to (R)Lip-EA-OH.
  • the broad peak eluting at about 15 minutes corresponds to the disulfide linked polymer of (R)Lip-EA-OH.
  • Two other impurities are observed to be present in this lot at ⁇ 0.4%, one of which is identified as R-lipoic acid.
  • FIG. 2 is a copy of an HPLC chromatogram of the 30 mg/mL (R)Lip-EA-OH formulation resulting from the revised formulation protocol described in Example 2.
  • the formulation contains ⁇ 0.1% polymer following formulation by adding (R)Lip-EA-OH to a solution of high pH and near final volume.
  • the chromatogram is enlarged to emphasize the products eluting in the baseline.
  • the peak eluting at 1 1.6 minutes corresponds to (R)Lip-EA- OH and the peak eluting at about 15.0 minutes corresponds to R-lipoic acid.
  • FIG. 3 is a bar graph of maximum CK-MB change from baseline as a function of treatment regimen (placebo or (R)Lip-EA-OH treatment at 0.8 mg/kg, 1.6 mg/kg or 2.4 mg/kg), and shows that patients in the (R)Lip-EA-OH treatment groups had less myocardial injury than patients in the placebo group, particularly at 2.4 mg/kg (R)Lip-EA-OH, following PCI.
  • FIG. 4 is a bar graph of troponin T change from baseline in the full analysis population (FAP) as a function of treatment regimen (placebo or (R)Lip-EA-OH treatment at 0.8 mg/kg, 1.6 mg/kg or 2.4 mg/kg), and shows that patients in the (R)Lip-EA-OH treatment groups had less myocardial injury than patients in the placebo group, particularly at 2.4 mg/kg (R)Lip-EA-OH, following PCI.
  • the disclosed compounds may exist in various stereoisomeric forms unless otherwise specified.
  • “Stereoisomers” are compounds that differ only in their spatial arrangement.
  • “Enantiomers” are pairs of stereoisomers that are non-superimposable mirror images of one another, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
  • Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.
  • R and S represent the configuration of substituents around one or more chiral carbon atoms.
  • Racemate or “racemic mixture,” as used herein, refers to a mixture containing equimolar quantities of two enantiomers of a compound. Such mixtures exhibit no optical activity (i.e., they do not rotate a plane of polarized light).
  • Percent enantiomeric excess is defined as the absolute difference between the mole fraction of each enantiomer multiplied by 100% and can be represented by the
  • the depicted or named enantiomer is present in an ee of at least or about 50%, at lest or about 60%, at least or about 70%, at least or about 80%, at least or about 90%, at least or about 95%, at least or about 98%, at least or about 99% or at least or about 99.9%.
  • the depicted or named diastereomer is present in a de of at least or about 50%, at least or about 60%, at least or about 70%, at least or about 80%, at least or about 90%, at least or about 95%, at least or about 98%, at least or about 99% or at least or about 99.9%.
  • (R)-LipoyP' refers to a compound containing a lipoyl moiety, wherein the stereocenter in the lipoyl moiety is in the (R) configuration.
  • An (R)-lipoyl moiety is pictured below:
  • (S)-LipoyP' refers to a compound containing a lipoyl moiety, wherein the stereocenter in the lipoyl moiety is in the (S) configuration.
  • An (S)-lipoyl moiety is pictured below:
  • Alkyl means a saturated aliphatic branched or straight-chain monovalent hydrocarbon radical having the specified number of carbon atoms.
  • (Ci-C 6 )alkyl means a radical having from 1 -6 carbon atoms in a linear or branched arrangement.
  • “(Ci- C 6 )alkyl” includes methyl, ethyl, propyl, / ' -propyl, butyl, /-butyl, /-butyl, sec-butyl, pentyl and hexyl.
  • alkyl has 1 to 20, 1 to 15, 1 to 10, 1 to 5 or 1 to 3 carbon atoms.
  • One or more hydrogen atoms of an alkyl group can be replaced with a substituent group. Suitable substituent groups include hydroxy, thio, halo, halo(Ci-C 3 )alkyl, (C
  • alkyl substituent groups include hydroxy and halo.
  • An alkyl can also be substituted with one or more acidic substituents selected from the group consisting of -C0 2 H, -S0 3 H, -P0 3 H 2 , -OSO3H, -OP0 3 H 2 , -B(OH) 2 and -NHOH.
  • alkoxy means -O-alkyl, where alkyl is as defined above.
  • thioalkyl means -S-alkyl, where alkyl is as defined above.
  • aryl means a carbocyclic aromatic ring.
  • (C 6 -Ci 4 )aryl includes phenyl, napthyl, indenyl, and anthracenyl. Typically, aryl has 6 to 20, 6 to 14, 6 to 10, 6 to 9, or 6 carbon atoms.
  • One or more hydrogen atoms of an aryl group can be replaced with a substituent group.
  • Suitable substituent groups include hydroxy, thio, halo, (C]-C 3 )alkyl,
  • aryl substituent groups include hydroxy and halo.
  • An aryl can also be substituted with one or more acidic
  • substantially separated or “substantially stereopure” means that the ee or de of the depicted or named compound is at least about 50%.
  • substantially separated or substantially stereopure can mean the ee or de of the depicted or named enantiomer is at least or about 50%, at least or about 60%, at least or about 70%, at least or about 80%, at least or about 90%, at least or about 95%, at least or about 98%, at least or about 99% or at least or about 99.9%.
  • substantially separated or substantially stereopure means that the ee or de of the depicted or named compound is at least or about 75%.
  • substantially separated means that the ee or de of the depicted or named compound is at least or about 90%.
  • substantially separated means that the ee or de of the depicted or named compound is at least or about 95%. In yet a more specific embodiment, substantially separated means that the ee or de of the depicted or named compound is at least or about 99%. In another specific embodiment, substantially separated means that the ee or de of the depicted or named compound is at least or about 99.9%.
  • amino acid means a molecule containing an amine group, a carboxylic acid group and a side chain which varies between different amino acids and includes both naturally-occurring amino acids and non-naturally-occurring amino acids. In one embodiment, "amino acid” is used to refer to naturally-occurring amino acids.
  • naturally-occurring amino acid means a compound represented by the formula NH 2 -CHR-COOH, wherein R is the side chain of a naturally- occurring amino acid such as an amino acid listed or named in the Table below.
  • “Naturally- occurring amino acid” includes both the D- and L- configuration.
  • diastereomer in which the one enantiomer or diastereomer is enriched relative to the other enantiomer or diastereomer(s), a racemic or diastereomeric mixture of the enantiomer or diastereomer(s) and mixtures enriched in one enantiomer or diastereomer relative to its corresponding optical isomer or other diastereomer(s).
  • Preferred naturally occurring amino acids include aspartic acid, tyrosine, glutamic acid and alanine.
  • Non-natural amino acid means an amino acid for which there is no nucleic acid codon.
  • non-natural amino acids include natural a-amino acids with non-natural side chains; ⁇ -amino acids (e.g., ⁇ -alanine); ⁇ -amino acids (e.g., ⁇ -aminobutryric acid).
  • the present invention relates in one embodiment to aqueous pharmaceutical formulations comprising a compound represented by Structural Formula (I) and/or (la).
  • R is (C,-C, 8 )alkyl, (C 6 -C 18 )aryl or (C 6 -Ci 8 )aryl(Ci-Ci 8 )alkyl and is substituted with at least one acidic substituent selected from the group consisting
  • aryl of the (C 6 -Ci 8 )aryl or (C -Ci 8 )aryl(Ci-Ci 8 )alkyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, (Ci-C 3 )alkyl, halo(Ci- C 3 )alkyl, cyano, nitro, (Ci-C 3 )alkoxy and thio(C 1 -C 3 )alkyl.
  • R is (Ci-Cig)alkyl and is substituted with at least one acidic substituent selected from the group consisting of
  • R is (Ci-C 3 )alkyl and is substituted with at least one acidic substituent selected from the group consisting of -C0 2 H, -SO 3 H, -P0 3 H 2 , -OS0 3 H, -OP0 3 H 2 , -B(OH) 2 and -NHOH.
  • R is (C 3 )alkyl and is substituted with at least one acidic substituent selected from the group consisting
  • R is (C 2 )alkyl and is substituted with at least one acidic substituent selected from the group consisting of -C0 2 H, -S0 3 H, -P0 3 H 2 , -OS0 3 H, -OP0 3 H 2 , -B(OH) 2 and -NHOH.
  • R is (Ci)alkyl and is substituted with at least one acidic substituent selected from the group consisting
  • R is (C 6 -Ci8)aryl and is substituted with at least one acidic substituent selected from the group consisting
  • R is (C 6 )aryl and is substituted with at least one acidic substituent selected from the group consisting
  • R is (C6-Ci 8 )aryl(Ci-Cig)alkyl and is substituted with at least one acidic substituent selected from the group consisting
  • aryl of the (C 6 -Ci 8 )aryl(Ci-Ci 8 )alkyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, (Ci-C3)alkyl, halo(Ci-C3)alkyl, cyano, nitro, (Ci-C 3 )alkoxy and thio(C
  • R is (C 6 )aryl(Ci-C3)alkyl and is substituted with at least one acidic substituent selected from the group consisting of -C0 2 H, -SO3H, -P0 3 H 2 , -OSO3H, -OPO3H2, -B(OH) 2 and -NHOH, wherein the aryl of the (C 6 )aryl(Ci-C3)alkyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, (Ci-C3)alkyl, halo(Ci-C3)alkyl, cyano, nitro, (Ci- C 3 )alkoxy and thio(d-C 3 )alkyl.
  • R is (C 6 )aryl(d-C 2 )alkyl and is substituted with at least one acidic substituent selected from the group consisting
  • aryl of the (C 6 )aryl(Ci-C2)alkyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, (C)-C3)alkyl, halo(C] -C3)alkyl, cyano, nitro, (Ci- C 3 )alkoxy and thio(C r C 3 )alkyl.
  • R is (C 6 )aryl(C2)alkyl and is substituted with at least one acidic substituent selected from the group consisting
  • R is (C 6 )aryl(Ci)alkyl and is substituted with at least one acidic substituent selected from the group consisting
  • aryl of the (C 6 )aryl(Ci)alkyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, (C
  • the at least one acidic substituent is selected from the group consisting of
  • the at least one acidic substituent is selected from the group consisting of
  • R is substituted with at least one acidic substituent selected from the group consisting of -C0 2 H, -SO3H, -P0 3 H 2 , -OSO3H, -OP0 3 H 2 , -B(OH) 2 and -NHOH.
  • R is substituted with one, two or three acidic substituents.
  • R is substituted with one or two acidic substituents.
  • Aryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halo, (Ci-C3)alkyl, halo(Ci-C3)alkyl, cyano, nitro, (Ci- C3)alkoxy and thio(Ci-C 3 )alkyl.
  • substituents selected from the group consisting of hydroxy, halo, (Ci-C3)alkyl, halo(Ci-C3)alkyl, cyano, nitro, (Ci- C3)alkoxy and thio(Ci-C 3 )alkyl.
  • aryl is further substituted with one, two or three substituents.
  • aryl is substituted with one substituent.
  • aryl is unsubstituted.
  • aryl is further substituted with one or more substituents selected from the group consisting of hydroxy or halo.
  • R 1 is hydrogen or (Ci-Cig)alkyl, wherein said (Ci-Ci 8 )alkyl is optionally
  • R' is hydrogen
  • R' is (Ci-C
  • R' is substituted with at least one acidic substituent selected from the group consisting of -C0 2 H, -SO3H, -P0 3 H 2 , -OSO3H, -OP0 3 H 2 , -B(OH) 2 and -NHOH.
  • R' is substituted with one, two or three acidic substituents.
  • R' is substituted with one or two acidic substituents. In a further embodiment, R' is substituted with one acidic substituent. Alternatively, R' is unsubstituted. [0050] X is absent or an amino acid, wherein the amino acid is oriented to form an amide
  • X is absent.
  • X is an amino acid.
  • X is a naturally-occurring amino acid.
  • X is aspartic acid, tyrosine, glutamic acid or alanine.
  • the compound is represented by Structural Formula (I) and/or (la), wherein the values and alternative values for the variables are as described above.
  • the (R)- lipoyl stereoisomer of a compound represented by Structural Formulas (I) or (la) is substantially separated from the (S)-lipoyl stereoisomer(s). Values and alternative values for the remainder of the variables are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment.
  • R' is H.
  • Values and alternative values for the remainder of the variables are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first aspect thereof.
  • R' is H and X is a naturally-occurring amino acid.
  • Values and alternative values for the remainder of the variables are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first or second aspect thereof.
  • R and R' are each (Ci-C 3 )alkyl substituted with one or two acidic substituents each independently selected from the group consisting of -C0 2 H, -S0 3 H, -P0 3 H 2 , -OS0 3 H and -OP0 3 H 2 .
  • Values and alternative values for the remainder of the variables are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first to third aspects thereof.
  • R' is H and X is absent.
  • Values and alternative values for the remainder of the variables are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first to fourth aspects thereof.
  • R is (Ci- C 3 )alkyl substituted with one or two acidic substituents each independently selected from the group consisting of -C0 2 H, -S0 3 H, -P0 3 H 2 , -OS0 3 H and -OP0 3 H 2 .
  • Values and alternative values for the remainder of the variables are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first to fifth aspects thereof.
  • R is (C 6 )aryl(Ci-C 3 )alkyl substituted with one or two acidic substituents each independently selected from the group consisting of -C0 2 H, -S0 3 H, -P0 3 H 2 , -OS0 3 H and -OP0 3 H 2 .
  • Values and alternative values for the remainder of the variables are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first to sixth aspects thereof.
  • R is (C 2 )alkyl substituted with one or two acidic substituents each independently selected from the group consisting of -C0 2 H, -S0 3 H, -P0 3 H 2 , -OS0 3 H and -OP0 3 H 2 .
  • Values and alternative values for the remainder of the variables are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first to seventh aspects thereof.
  • R is (C 6 )aryl substituted with one acidic substituent selected from the group consisting
  • the compound is represented by Structural Formula (I), wherein the values and alternative values are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first to ninth aspects thereof.
  • the compound is represented by Structural Formula (la), wherein the values and alternative values are as described above for Structural Formulas (I) or (la) or in the 1 st specific embodiment, or first to tenth aspects thereof.
  • the compound is represented by any one of the structural formulas in Table A.
  • the (R)- lipoyl stereoisomer of any of the compounds in Table A is substantially separated from the (S)-lipoyl stereoisomer s).
  • the compound is represented by the following structural formula:
  • the (R)-lipoyl stereoisomer of the compound of Structural Formula II or Ila is substantially separated from the (S)-lipoyl stereoisomer(s).
  • aqueous pharmaceutical formulations comprising a lipoyl compound that is substituted with at least one acidic substituent, such as a compound of Structural Formula I, la, II, Ila; and an inorganic base in an amount sufficient to deprotonate each acidic substituent in lipoyl compound, wherein the formulation has a pH of from about 6.5 to about 8.0 and a tonicity of from about 250 mOsm to about 350 mOsm.
  • Aqueous pharmaceutical formulation refers to a water-containing solution or suspension of sufficient purity and quality such that, when administered to a patient, such as a human or animal, the active ingredient(s) of the formulation typically exert a desired therapeutic effect ⁇ e.g., prevent the onset of; alleviate, partially or substantially or totally, the symptoms of; or delay, inhibit or stop the progression of a disorder or disease being treated).
  • aqueous pharmaceutical formulation should typically not produce an adverse reaction.
  • a lipoyl compound is present in a formulation of the invention in a concentration of from about 5 mg/mL to about 50 mg/mL, from about 10 mg/mL to about 40 mg/mL, from about 9 mg/mL to about 30 mg/mL or of about 25 mg/mL.
  • an aqueous pharmaceutical formulation comprising a lipoyl compound is substantially free of polymerized derivative(s) of the lipoyl compound.
  • Lipoyl compounds have a propensity to form impurities, such as polymers, upon exposure to light to form polymerized derivatives of lipoyl compounds.
  • impurities such as polymeric derivative(s) of lipoyl compounds
  • the formation of impurities, such as polymeric derivative(s) of lipoyl compounds is proposed to proceed by photolytic opening of the dithiolane ring resulting in a diradical, followed by propagation through intermolecular disulfide bond formation.
  • Polymerized derivative(s) of the lipoyl compound refers to derivative(s) of a lipoyl compound that contain two or more lipoyl moieties. In some cases, the polymerized derivatives have a molecular weight of greater than about 3,500 Daltons.
  • substantially free means that a formulation contains less than about 5% of an indicated impurity or indicated impurities in the formulation ⁇ e.g., polymerized derivative(s) of the lipoyl compound in the formulation, lipoic acid).
  • a formulation is substantially free of all impurities ⁇ e.g. , polymerized derivative(s) of the lipoyl compound in the formulation and lipoic acid).
  • Impurities can be represented by a single chemical species ⁇ e.g. , (R)-lipoic acid) or several different chemical species ⁇ e.g. , polymerized derivatives of the lipoyl compound in the formulation, (R)-lipoic acid, etc.).
  • a formulation can contain less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% of an indicated impurity or indicated impurities ⁇ e.g., polymerized derivative(s) of the lipoyl compound in the formulation) or all impurities ⁇ e.g., polymerized derivative(s) of the lipoyl compound in the formulation and lipoic acid).
  • the formulation contains less than about 1%, preferably, less than about 0.5%, more preferably, less than about 0.25%, yet more preferably, less than about 0.1% of polymerized derivative(s) of the lipoyl compound in the formulation.
  • the purity of a formulation comprising a lipoyl compound can be assessed in terms of the amount ⁇ e.g. , concentration) of desired lipoyl compound (including
  • the measurement of the purity of a formulation comprising a lipoyl compound is a measurement distinct from the measurement of the stereopurity of the lipoyl compound in the formulation.
  • Impurities include, but are not limited to, other lipoyl- containing compounds of different structural formulas ⁇ e.g. , polymerized derivative(s) of the lipoyl compound, other lipoyl compounds).
  • the purity of a formulation comprising a lipoyl compound is assessed in terms of the amount of the lipoyl compound compared to the amount of other lipoyl-containing compounds of different structural formulas.
  • the purity of a formulation disclosed herein can be at least or about 95%, at least or about 98%, at least or about 99%, at least or about 99.5% or at least or about 99.9%.
  • the purity of a formulation or the amount of impurities in a formulation can be measured, for example, using the assay of chemical purity described in the Exemplification.
  • "Inorganic base,” as used herein, includes both bases that contain no carbon atom and inorganic carbon bases that contain carbon-carbon or carbon-hydrogen bond(s), but not both.
  • the choice of inorganic base is not particularly limited, except that the base should be able to deprotonate an acidic substituent in a lipoyl compound.
  • Exemplary inorganic bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and sodium bicarbonate.
  • Sodium hydroxide is a particularly preferred inorganic base.
  • the inorganic base is a sodium base.
  • Sodium base refers to any inorganic sodium salt that dissociates in aqueous solution into a sodium cation and an anion capable of deprotonating an acidic substituent in a lipoyl compound.
  • Exemplary sodium bases include sodium hydroxide, sodium carbonate and sodium bicarbonate.
  • the inorganic base is a hydroxide base.
  • “Hydroxide base” refers to any inorganic base, typically an ionic base (e.g., a salt), that dissociates in aqueous solution into a hydroxide anion and a cation.
  • exemplary hydroxide bases include sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, lithium hydroxide, etc.
  • Preferred hydroxide bases include sodium hydroxide, potassium hydroxide and calcium hydroxide.
  • a compound of Structural Formula II contains two acidic substituents, one in the portion of the compound of Structural Formula I designated as variable X and one in the portion of a compound of Structural Formula I designated as R or R'.
  • "An amount sufficient to deprotonate each acidic substituent" refers to an amount of an inorganic base (e.g.
  • a compound of Structural Formula II contains two acidic substituents. Therefore, an amount sufficient to deprotonate each acidic substituent in a compound of Structural Formula II is an amount approximately equal to or greater than two molar equivalents of a compound of Structural Formula II. In other words, at least about two molar equivalents of an inorganic base should be present in an aqueous pharmaceutical formulation of the invention in order to deprotonate the acidic substituents present in a compound of Structural Formula II.
  • a formulation comprises an inorganic base in an amount that is greater than the molar equivalents of the acidic substituent(s) in a lipoyl compound.
  • a formulation comprises inorganic base (e.g., sodium base, hydroxide base, sodium hydroxide) in a concentration of from about 25 mg/n L to about 200 mg/mL, from about 50 mg/niL to about 150 mg/mL or of about 125 mg/mL.
  • inorganic base e.g., sodium base, hydroxide base, sodium hydroxide
  • Tonicity is the effective osmolality of a solution and is equal to the sum of the concentrations of the solutes which have the capacity to exert an osmotic force across a membrane, such as a cell membrane. Osmolality is the measure of the number of osmoles of solute per kilogram of solvent in a solution.
  • the pharmaceutical formulations described herein can be isotonic, hypotonic or hypertonic.
  • the aqueous pharmaceutical formulations described herein are isotonic.
  • Isotonic formulations are formulations that have essentially the same osmotic pressure as human blood, for example, osmotic pressure of from about 260 mOsm to about 320 mOsm.
  • Slightly hypotonic formulations having a slightly lower osmotic pressure, for example, osmotic pressure of from about 250 mOsm to less than 260 mOsm.
  • Slightly hypertonic formulations have a slightly higher osmotic pressure, for example, osmotic pressure of greater than 320 to about 350.
  • Methods of measuring tonicity are well-known in the art and include melting point depression.
  • an aqueous pharmaceutical formulation has a tonicity of from about 250 mOsm to about 350 mOsm.
  • an aqueous pharmaceutical formulation has a tonicity of from about 260 mOsm to about 320 mOsm.
  • a tonicity agent can be used to achieve and/or maintain the tonicity of an aqueous pharmaceutical formulation.
  • an aqueous pharmaceutical formulation further comprises a tonicity agent.
  • a tonicity agent should be present in a formulation in an amount sufficient to achieve and/or maintain a tonicity of from about 250 mOsm to about 350 mOsm or, preferably, from about 260 mOsm to about 320 mOsm.
  • a tonicity agent is preferably present at levels that are in accordance with the Food and Drug Administration's Inactive Ingredient Database for IV formulations.
  • a tonicity agent can be non-ionic or ionic.
  • non-ionic tonicity agents include polyols, such as glycerin, glycerol, mannitol or erythritol; amino acids; and sugars, such as dextrose.
  • Ionic tonicity agents include sodium chloride and potassium chloride.
  • a formulation comprises a tonicity agent ⁇ e.g. , an ionic tonicity agent such as sodium chloride) in a concentration of from about 1 mg/mL to about 10 mg/mL, from about 2.5 mg/mL to about 7.5 mg/mL, from about 3.5 mg/mL to about 6 mg/mL or of about 6 mg/mL.
  • a tonicity agent e.g. , an ionic tonicity agent such as sodium chloride
  • an aqueous pharmaceutical formulation further comprises a buffer.
  • a buffer should be present in a formulation in an amount sufficient to achieve and/or maintain a pH of from about 6.5 to about 8.0, preferably, from about 6.8 to about 7.6, more preferably, from about 7.0 to about 7.2.
  • Exemplary buffers include phosphate, phosphate-buffered saline, succinate, gluconate, histidine, citrate, MES, ADA, PIPES, ACES, MOPSO, cholamine chloride, MOPS, BES, TES, HEPES, DIPSO, acetamidoglycine, TAPSO, POPSO, HEPPSO, HEPPS, tricine, glycinamide, bicine and TAPS.
  • a particularly preferred buffer is phosphate buffer, for example, sodium phosphate buffer or sodium phosphate dibasic.
  • a formulation comprises a buffer (e.g. , phosphate buffer, such as sodium phosphate dibasic) in a concentration of from about 0.5 mg/mL to about 5 mg/mL, from about 1 mg/mL to about 3 mg/mL, from about 1.4 mg/mL to about 2.7 mg/mL or of about 1.4 mg/mL.
  • a buffer e.g. , phosphate buffer, such as sodium phosphate dibasic
  • the formulation comprises from about 5 mg/mL to about 50 mg/mL of a lipoyl compound; and from about 25 mg/mL to about 200 mg/mL sodium hydroxide.
  • the formulation has a pH of from about 7.0 to about 7.2 and a tonicity of from about 260 mOsm to about 320 mOsm.
  • the formulation comprises from about 9 mg/mL to about 30 mg/mL of a compound for use in the formulations of the invention, and from about 50 mg/mL to about 150 mg/mL sodium hydroxide; and has a pH of from about 7.0 to about 7.2 and a tonicity of from about 260 mOsm to about 320 mOsm.
  • aqueous pharmaceutical formulations comprising from about 5 mg/mL to about 30 mg/mL of a compound represented by Structural Formula Ila; from about 25 mg/mL to about 200 mg/mL sodium hydroxide; buffer; and a tonicity agent.
  • the formulations have a pH from about 6.8 to about 7.6 and a tonicity of from about 260 mOsm to about 320 mOsm. Concentrations and alternative concentrations for the
  • the formulation comprises about 25 mg/mL of the compound of Structural Formula Ila; about 125 mg/mL sodium hydroxide; sodium phosphate buffer; and sodium chloride, wherein the formulation has a pH of from about 7.0 to about 7.2 and a tonicity of from about 260 mOsm to about 320 mOsm.
  • aqueous pharmaceutical formulations described herein are typically intended for parenteral (e.g., intraarticular, intramuscular, intravenous, intraventricular, intraarterial, intrathecal, subcutaneous, or intraperitoneal) and, in particular, intravenous administration.
  • parenteral e.g., intraarticular, intramuscular, intravenous, intraventricular, intraarterial, intrathecal, subcutaneous, or intraperitoneal
  • the formulations described herein can be described as intravenous aqueous pharmaceutical formulations.
  • the pharmaceutical formulations can be transferred, preferably aseptically, into an appropriate container, for example, an amber vial to provide a suitable dosage of the lipoyl compound.
  • Suitable intravenous dosages of a lipoyl compound in a formulation of the invention can be from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about 1 mg/kg to about 5 mg/kg or from about 2 mg/kg to about 3 mg/kg body weight per treatment.
  • an aqueous pharmaceutical formulation e.g., an aqueous pharmaceutical formulation having a pH of from about 6.5 to about 8.0 and a tonicity of from about 250 mOsm to about 350 mOsm
  • a lipoyl compound (Structural Formula I, la, II, Ila, etc.).
  • the process comprises providing a lipoyl compound (which is substituted with at least one acidic substituent); and providing an aqueous solution comprising an inorganic base in an amount sufficient to deprotonate each acidic substituent in the lipoyl compound.
  • the volume of the aqueous solution is equal to or greater than about 75% of the volume of the formulation.
  • the lipoyl compound is added to the aqueous solution, thereby forming a pharmaceutical solution, and the pharmaceutical solution is diluted to the volume of the formulation with a diluent to thereby prepare the aqueous pharmaceutical formulation.
  • Concentrations and alternative concentrations for the components of this formulation, as well as particular lipoyl compounds and inorganic bases, alternative pH and tonicity ranges and additional components and concentrations thereof, are as described and defined hereinabove with respect to formulations.
  • a variety of diluents can be used to dilute the pharmaceutical solution, provided that the diluent forms, in combination with the other elements in the formulation, a pharmaceutically acceptable formulation.
  • the formulation comprises buffer
  • an aliquot of the buffer can be employed for the dilution.
  • an aliquot of the aqueous solution can be used as the diluent.
  • the diluent is water.
  • the formulation comprising a lipoyl compound is substantially free of polymerized derivatives of the lipoyl compound, wherein "substantially free” is as described above with respect to formulations of the invention.
  • the process further comprises adjusting the pH of the aqueous solution and/or pharmaceutical solution and/or pharmaceutical formulation.
  • an acid such as hydrochloric acid
  • hydrochloric acid can be added to an aqueous solution and/or pharmaceutical solution and/or pharmaceutical formulation to acidify the solution and thereby form a formulation having the desired pH.
  • the volume of the aqueous solution is equal to or greater than about 80%, equal to or greater than about 85%, equal to or greater than about 90% or equal to or greater than about 95% of the volume of the formulation.
  • the aqueous solution further comprises a buffer, for example, phosphate buffer.
  • the amount of buffer in the aqueous solution is an amount sufficient (either alone or in combination with other components of the formulation, such as the diluent) to achieve a formulation having the desired concentration of buffer.
  • the aqueous solution further comprises a tonicity agent, for example, an ionic tonicity agent such as sodium chloride.
  • a tonicity agent for example, an ionic tonicity agent such as sodium chloride.
  • the amount of tonicity agent in the aqueous solution is an amount sufficient (either alone or in combination with other components of the formulation) to form a formulation comprising the desired concentration of tonicity agent.
  • Alternative tonicity agents as well as exemplary
  • concentrations of tonicity agents are as described and defined hereinabove with respect to the formulations.
  • the process further comprises adjusting the tonicity of the aqueous solution and/or pharmaceutical solution and/or pharmaceutical formulation.
  • Tonicity can be adjusted, for example, by adding a tonicity agent to the aqueous solution, for example, in an amount (either alone or in combination with other components of the formulation) sufficient to form a formulation comprising the desired concentration of tonicity agent.
  • the aqueous pharmaceutical formulation has a pH of from about 6.5 to about 8.0 and a tonicity of from about 250 mOsm to about 350 mOsm.
  • the concentration of each component of the aqueous or pharmaceutical solution or, indeed, the pH or tonicity of the aqueous or pharmaceutical solution is likely not the concentration (or pH or tonicity) of the pharmaceutical formulation.
  • concentration or pH or tonicity
  • the lipoyl compound is added to the aqueous solution in an amount sufficient to form a formulation comprising from about 5 mg/mL to about 50 mg/mL.
  • the volume of the aqueous solution is 90% of the volume of the formulation and a concentration of lipoyl compound of 10 mg/mL is desired
  • 10 g of lipoyl compound should be added to, for example, 900 mL of aqueous solution, such that dilution with 100 mL of diluent will result in a formulation having 10 mg/mL lipoyl compound.
  • the lipoyl compound is added to the aqueous solution in an amount sufficient to form a formulation comprising from about 5 mg/mL to about 50 mg/mL, from about 10 mg/mL to about 40 mg/mL, from about 9 mg/mL to about 30 mg/mL or about 25 mg/mL of the lipoyl compound.
  • the amount of inorganic base in the aqueous solution is an amount sufficient (either alone or in combination with other components of the formulation, such as the diluent) to form a formulation comprising from about 25 mg/mL to about 200 mg/mL or from about 50 mg/mL to about 150 mg/mL inorganic base.
  • the amount of inorganic base in the aqueous solution is the amount sufficient to form a formulation having the desired concentration of inorganic base.
  • the aqueous solution comprises a sufficient amount of inorganic base such that additional inorganic base need not be included in the diluent to achieve a formulation comprising the desired concentration of inorganic base.
  • the lipoyl compound is added to the aqueous solution in an amount sufficient to form a formulation comprising from about 5 mg/mL to about 50 mg/mL of the lipoyl compound;
  • the inorganic base is sodium hydroxide and the amount of sodium hydroxide in the aqueous solution is an amount sufficient to form a formulation comprising from about 25 mg/mL to about 200 mg/mL sodium hydroxide; and the formulation has a pH of from about 7.0 to about 7.2 and a tonicity of from about 260 mOsm to about 320 mOsm.
  • the lipoyl compound is added to the aqueous solution in an amount sufficient to form a formulation comprising from about 9 mg/mL to about 30 mg/mL of the lipoyl compound; and the amount of sodium hydroxide in the aqueous solution is an amount sufficient to form a formulation comprising from about 25 mg/mL to about 200 mg/mL sodium hydroxide.
  • a process for preparing an aqueous pharmaceutical formulation comprising a compound of Structural Formula Ila.
  • the process comprises providing an aqueous solution comprising a buffer, a tonicity agent and sodium hydroxide; adding a compound represented by Structural Formula Ila to the aqueous solution in an amount sufficient to form a formulation comprising from about 5 mg/mL to about 50 mg/mL of the compound of Structural Formula Ila, thereby forming a pharmaceutical solution; and diluting the pharmaceutical solution to the volume of the formulation with a diluent, thereby preparing the aqueous pharmaceutical formulation having a pH from about 6.8 to about 7.6 and a tonicity of from about 260 mOsm to about 320 mOsm.
  • the amount of sodium hydroxide in the aqueous solution is an amount sufficient to form a formulation comprising from about 25 mg/mL to about 200 mg/mL sodium hydroxide and the volume of the aqueous solution is equal to or greater than about 75% of the volume of the formulation.
  • the aqueous solution comprises sodium phosphate buffer, sodium chloride and sodium hydroxide.
  • Compound of Structural Formula Ila is added to the aqueous solution in an amount sufficient to form a formulation comprising about 25 mg/mL compound of Structural Formula Ila and the amount of sodium hydroxide in the aqueous solution is an amount sufficient to form a formulation comprising about 125 mg/mL sodium hydroxide.
  • aqueous pharmaceutical formulation made according to any of the processes described herein.
  • HPLC performance liquid chromatography
  • Mobile phase A was 0.1% triflouroacetic acid (TFA) in H 2 0 and mobile phase B was 0.1% TFA in acetontrile (ACN).
  • a lipoyl compound was diluted in ethanol: water (1 :1) at a concentration of 1 mg/mL and a 25 ⁇ ⁇ aliquot was injected onto the HPLC. The sample was detected at 220 nm.
  • RLipoic acid (RLip-OH - 50,0 g - 0.242 mol) was added to a 2L round-bottomed flask containing 500mL acetone and mixed with magnetic stirring until dissolved. The solution was protected from direct light by covering the flask with foil. N,N- Diisopropylethylamine (DIEA - 42.2 mL - 0.242 mol) and NN'-disuccinimidylcarbonate (DSC - 77.6 g - 0.303 mol) were added sequentially and the reaction was stirred vented for 3 hours at room temperature.
  • DIEA Diisopropylethylamine
  • DSC NN'-disuccinimidylcarbonate
  • the solution was rapidly stirred and acidified by the slow addition of 0.25 N sulfuric acid, then 0.5 N sulfuric acid, until the pH was measured at 2.0.
  • the combined solution was transferred to a separatory funnel and allowed to settle.
  • the aqueous solution was removed and the product- containing organic solution was washed one time with water (250 mL).
  • the product was immediately recrystallized by dissolving the isolated RLip-EA- OH wet cake in a prepared mixed solution of IP A (190 mL), IpOAc (1000 mL), and water (60 mL). This solution was passed through a medium porosity fritted glass filter and transferred to a round-bottomed flask. The volume of the solution was reduced on a rotary evaporator with a bath temperature of 42 °C. After 650 mL of the organic solution had been removed, an additional 650 mL of IpOAc was charged to the 2L flask and the solution again reduced in volume on the rotary evaporator. Product began to crystallize from solution after the removal of approximately 600 mL.
  • (R)Lip-EA-OH was analyzed by HPLC using the assay for purity described above. RLip-EA-OH was isolated in a 38% overall yield (47.2 g - 0.1 16 mol) at >98% purity (HPLC area percent).
  • Example 2 Process for Making a 30mg/mL (R)Lip-EA-OH Formulation
  • a 30 mg/mL (R)Lip-EA-OH formulation formulated according to the revised procedure contained ⁇ 0.1% polymer by analysis of the HPLC area counts. Analysis of the HPLC chromatogram indicated that polymerization of (R)Lip-EA-OH did not occur to any significant extent during formulation using the revised protocol ⁇ see FIG. 2).
  • the resulting drug formulation was a pH neutral isotonic saline solution of (R)Lip- EA-OH. Since (R)Lip-EA-OH contains two carboxylic acid functions, treatment with an aqueous sodium bicarbonate or sodium hydroxide solution provides a highly water soluble bis-sodium salt of (R)Lip-EA-OH. Typically, formulations comprising up to about 30 mg/mL (R)Lip-EA-OH are isotonic, whereas formulation comprising greater than about 30 mg/mL (R)Lip-EA-OH are hypertonic.
  • a 10 mg/mL (R)Lip-EA-OH formulation was prepared using the general revised formulation protocol described in Example 2. Details of the formulation are given in Table 1 and Table 2.
  • Stability data for a representative 7,500-mL batch of the 10 mg/mL (R)Lip-EA- OH formulation is shown in Table 2 A and Table 2B.
  • Table 2 A 10 mg/mL Stability Data for a 10 mg/mL ( )Lip-EA-OH Batch at 5 ⁇ 3°C.
  • ⁇ Vials were stored inverted. A set of vials were turned upright and tested at the 3 and 4 month time points. The limitation on the number of bottles placed under stability conditions did not permit for turning more bottles upright for testing at additional time periods.
  • (R)Lip-EA-OH was then added to the vessel. The solution was stirred for 1 hour or until the solid dissolved. If required, the pH of the solution was adjusted using 1 N sodium hydroxide or 1 N hydrochloric acid to 7.1 + 0.1. Sterile water for injection (WFI) was added to final weight. Osmolality and pH were evaluated and, if required, the pH of the solution was adjusted using 1 N NaOH (aq) or 1 N HC1 (aq) to 7.1 + 0.1. An aseptic transfer was performed followed by an aseptic fill consisting of 18 mL of (R)Lip-EA-OH dose formulation into individual 20 mL amber vials. The vials were purged with argon, sealed, inspected and then labeled.
  • WFI Sterile water for injection
  • Acute myocardial infarction and acute stroke are manifestations of sudden occlusion of vessels of the coronary and cerebral circulations, respectively; the morbidity and mortality of these conditions are a direct manifestation of cell injury and death.
  • Loss of cellular perfusion leading to cell injury and death is a common pathophysiologic mechanism for both natural disease states and operative procedures. Given the necessary interruption of blood flow to the heart during (on-pump) coronary bypass surgery and with major organ transplantation, ischemia-mediated cellular damage also frequently complicates these procedures.
  • PCI percutaneous coronary intervention
  • stent placement both balloon inflation and downstream embolization due to dislodged plaque can lead to ischemic injury.
  • reperfusion therapy such as coronary artery bypass grafting (CABG) or PCI for ischemic heart disease
  • CABG coronary artery bypass grafting
  • PCI for ischemic heart disease
  • reperfusion itself may result in deleterious effects, including cardiomyocyte death, microvascular injury, myocardial stunning, and arrhythmias.
  • Emerging data suggest that distal embolization of atherothrombotic material accompanying balloon-induced plaque disruption results in impaired microcirculatory flow and ventricular dysfunction.
  • cardiac enzymes are measured after PCI, up to 30% of patients have elevated levels of CK-MB or other evidence of periprocedural myocardial injury, and similar proportions of patients develop electrocardiographic changes.
  • the contribution of inflammation and endothelial injury is less clear, the final common pathway is potentially irreversible cardiomyocyte injury that manifests clinically as adverse events, including increased mortality.
  • the (R)Lip-EA-OH formulation was made in accordance with Example 3 and was administered at one of three doses: 0.8 mg/kg, 1.6 mg/kg and 2.4 mg/kg.
  • the primary objective was to assess the safety of the (R)Lip-EA-OH formulation, ascertained by measuring the changes in CK-MB values up to 24 hours after the last balloon inflation.
  • the secondary objective was to evaluate reduction of myocardial injury associated with stent PCI, as determined by serial measurements of cardiac biomarkers and as determined by continuous and serial ECG readings.
  • (R)Lip-EA-OH treatment demonstrated efficacy in reducing the myocardial injury and has shown cardioprotective action.
  • the efficacy markers of periprocedural injury such as changes in levels of Troponin-T, CK-MB AUC 0-24 and C max of CK-MB were lowest in the 2.4 mg/kg dose group.
  • CK-MB Efficacy. The primary outcome measure was the change in CK-MB at 24 hours after the last balloon inflation and it served as a surrogate marker for myocardial injury considered for safety and efficacy. CK-MB levels were measured on Day 1 at 0, 6, 12, 18, and 24 hours after the last balloon inflation.
  • N Number of subjects with CKMB at the given time point. Baseline is the value from the Screening visit. (1 ] p-values from a repeated measures ANOVA model on the with-in group change from baseline values with a term for time point. In essence this is a paired t-test that takes into account the repeated measurements within a subject.
  • C max The maximum serum concentration of CK-MB (C max ) is calculated by subtracting the baseline value from the maximum concentration of CK-MB measured at any time point.
  • CK-MB Cmax is correlated to the extent of myocardial injury associated with the PCI.
  • the greatest C max value observed was in the placebo group.
  • C max as an indicator of injury, the greatest injury was observed in the placebo group while the least amount of injury was observed in the 2.4 mg/kg dose group, followed by the 0.8 mg/kg dose and 1.6 mg/kg dose groups, respectively.
  • TnT Troponin-T
  • N Number of subjects with Troponin-T at the given time point. At Baseline, most of the measurements were below the level of detection (which is 0.001). Hence, statistics are shown with three digits.
  • N Number of subjects with Troponin-T at the given time point. Baseline is the value from the Screening visit. At Baseline most of the measurements were below the level of detection (which is 0.001) hence statistics are shown with three digits.

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Abstract

La présente invention concerne des formulations pharmaceutiques aqueuses comprenant des composés de lipoyle, tels que des composés de formule structurale (I) : les formulations comprennent un composé de lipoyle comprenant au moins un substituant acide; et une base inorganique dans une quantité suffisante pour déprotoner chaque substituant acide dans le composé de lipoyle. Dans certains modes de réalisation, les formulations ont un pH d'environ 6,5 à environ 8,0 et une tonicité d'environ 250 mOsm à environ 350 mOsm.
PCT/US2014/000090 2014-05-14 2014-05-14 Formulations comprenant des composés de lipoyle WO2015174948A1 (fr)

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WO2018200680A1 (fr) 2017-04-25 2018-11-01 Ischemix Llc Compositions et procédés pour le traitement d'une lésion cérébrale traumatique

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US9540417B2 (en) 2009-05-14 2017-01-10 Ischemix Llc Compositions and methods for treating ischemia and ischemia-reperfusion injury
WO2018200680A1 (fr) 2017-04-25 2018-11-01 Ischemix Llc Compositions et procédés pour le traitement d'une lésion cérébrale traumatique
US10744115B2 (en) 2017-04-25 2020-08-18 Ischemix Llc Compositions and methods for treating traumatic brain injury
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