WO2024102699A1 - Formulations de stimulateur de guanylate cyclase (gc) et leurs utilisations - Google Patents

Formulations de stimulateur de guanylate cyclase (gc) et leurs utilisations Download PDF

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Publication number
WO2024102699A1
WO2024102699A1 PCT/US2023/078897 US2023078897W WO2024102699A1 WO 2024102699 A1 WO2024102699 A1 WO 2024102699A1 US 2023078897 W US2023078897 W US 2023078897W WO 2024102699 A1 WO2024102699 A1 WO 2024102699A1
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stimulator
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total
months
pharmaceutical formulation
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PCT/US2023/078897
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English (en)
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Jared STEFANICK
Stefan Hofmann
Martina Rehagen
Gerald Beddies
Iris Heep
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ELANCO US, Inc.
Elanco Animal Health Gmbh
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Publication of WO2024102699A1 publication Critical patent/WO2024102699A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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

Definitions

  • the present disclosure relates to formulations for treating hypertension and/or associated diseases. More specifically, the present disclosure relates to formulations comprising a therapeutically effective amount of a guanylate cyclase (GC) stimulator of Formula (I): or a pharmaceutically acceptable salt thereof.
  • GC guanylate cyclase
  • Hypertension refers to a condition where the blood pressure (the force of the blood pushing against the artery walls) is persistently elevated.
  • Hypertension may be defined by systolic blood pressure, diastolic blood pressure, and/or mean arterial blood pressure.
  • Felines may be considered to be hypertensive when they present with a systolic blood pressure of greater than about 150 mm Hg, for example.
  • Canines may be considered to be hypertensive when they present with a systolic blood pressure of greater than about 160 mm Hg, for example.
  • Equines may be considered to be hypertensive when they present with a systolic blood pressure of greater than about 115 mm Hg, for example.
  • Hypertension can increase the risk of many serious medical conditions, such as heart attack, stroke, and kidney disease, and organ damage, among others.
  • Guanylate cyclase (GC) stimulators is a group of compounds that can mitigate hypertension. GC stimulators can enhance the activity of guanylate cyclase (GC), an enzyme that relaxes vascular smooth muscles, thereby increasing the diameter of blood vessels and decreasing blood pressure.
  • GC guanylate cyclase
  • GC stimulators may be very sensitive to UV and/or visible (VIS) radiation or susceptible to hydrolysis.
  • VIS visible
  • the subject being treated may be unwilling to take the medicine voluntarily due to an unpleasant taste.
  • a pharmaceutical formulation for treating hypertension and/or associated diseases comprising: a therapeutically effective amount of a guanylate cyclase (GC) stimulator, wherein the GC stimulator is a compound of Formula (I): or a pharmaceutically acceptable salt thereof.
  • GC guanylate cyclase
  • the pharmaceutical formulation may be an oral suspension, an oral solution, a solution suitable for intravenous and/or parenteral administration, or a topical medication.
  • the pharmaceutical formulation may be an oral suspension.
  • the pharmaceutical formulation is an oral suspension that is water-based or oil-based.
  • the oral suspension may have a pH value of between about 4.6 and about 9.4, between about 4.7 to 9.3, between about 4.8 and about 9.2, between about 4.9 and about 9.1 , between about 5.0 and about 9.0, between about 5.1 and about 8.9, between about 5.3 and about 8.8, between about 5.4 and about 8.7, between about 5.5 and about 8.6, between about 5.6 and about 8.5, between about 5.7 and about 8.4, between about 5.8 and about 8.3, between about 5.9 and about 8.2, between about 6.0 and about 8.1 , between about 6.1 and about 8.0, between about 6.0 and about 7.9, between about 6.1 and about 7.8, between about 6.2 and about 7.7, between about 6.3 and about 7.7, between about 6.4 and about 7.6, between 6.5 and
  • SUBSTITUTE SHEET (RULE 26) about 7.5, between about 6.6 and about 7.4, between about 6.7 and about 7.3, between about 6.8 and about 7.2, between about 6.9 and about 7.1 , between about 4.6 and about 8.3, between about 4.7 and about 8. 3, between about 4.8 and about 8.0, between about 4.9 and about 8.0, between about 5.0 and about 8.0, between about 5.1 and about 8.0, between about 5.2 and about 8.0, between about 5.3 and about 8.0, between about 5.4 and about 8.0, between about 5.5 to 8.0, between about 5.6 and about 8.0, between about
  • the pharmaceutical formulation may comprise between about 0.1 and about 2 w/v%, between about 0.25 and about 1 .75 w/v%, between about 0.5 and about 1 .5 w/v%, between about 1 and about 1 .25 w/v%, about 0.1 w/v%, about 0.25 w/v%, about 0.5 w/v%, about 0.75 w/v%, about 1 w/v%, about 1 .5 w/v%, about 1 .75 w/v%, or about 2 w/v% of the GC stimulator.
  • the pharmaceutical formulation may further comprise: (i) a total of between about 0.01 and about 10 w/v%, between about 0.1 and about 9 w/v%, between about 0.25 and about 8 w/v%, between about 0.5 and about 7 w/v%, between about 0.75 and about 6 w/v%, between about 1 .0 and about 5 w/v%, between about 1 .25 and about 4 w/v%, between about 1 .5 and about 3 w/v%, or between about 0.1 and about 2 w/v% of one or more buffer; (ii) a total of between about 0.01 and about 5 w/v%,
  • SUBSTITUTE SHEET (RULE 26) between about 0.05 and about 4 w/v%, between about 0.075 and about 3 w/v%, between about 0.1 and about 2 w/v%, between about 0.125 and about 1 w/v%, between about 0.15 and about 0.75 w/v%, or between about 0.2 and about 0.5 w/v% of one or more acid; (iii) a total of between about 0.01 and about 5 w/v%, between about 0.25 and about 4 w/v%, between about 0.5 and about 3 w/v%, between about 0.75 and about 2 w/v%, between about 1 and about 1 .75 w/v%, between about 0.15 and about 1 .5 w/v%, between about 0.2 and about 2.0 w/v%, between about 0.3 and about 1.9 w/v%, between about 0.4 and about 1 .8 w/v%, between about 0.5 and about 1 .7 w/v%, between about 0.6
  • w/v% between about 0.8 and about 2.3 w/v%, between about 0.9 and about 2.2 w/v%, between about 1.0 and about 2.1 w/v%, between about 1.1 and about 2.0 w/v%, between about 1.2 and about 1 .9 w/v%, between about 1 .3 and about 1.8 w/v%, between about 1 .4 and about 1 .7 w/v%, or between about 1 .5 and about 1 .6 w/v% of one or more preservative; (vi) a total of between about 0.01 and about 5 w/v%, between about 0.01 and about 4 w/v%, between about 0.05 and about 3 w/v%, between about 0.075 and about 2 w/v%, between about 0.1 and about 1 w/v%, between about 0.01 and about 0.2 w/v%, between about 0.05 and about 0.1 w/v%, between about 0.1 and about 0.125 w/v%, between
  • SUBSTITUTE SHEET (RULE 26) or between about 0.9 and about 1.1 w/v% of one or more thickener; (viii) a total of between about 0.05 and about 10 w/v%, between about 0.1 and about 9 w/v%, between about 0.25 and about 8 w/v%, between about 0.5 and about 7 w/v%, between about 0.75 and about 6 w/v%, between about 1 .0 and about 5 w/v%, between about 1 .25 and about 4 w/v%, between about 1.5 and about 3 w/v%, or between about 0.1 and about 2 w/v% of one or more additive for pH adjustment; and/or (ix) a total of between about 0.01 and about 5 w/v%, between about 0.01 and about 4 w/v%, between about 0.05 and about 3 w/v%, between about 0.075 and about 2 w/v%, between about 0.1 and about 1 w/v%, between about 0.01 and about
  • the pharmaceutical formulation may further comprise (i) a total of 0.1-2 w/v% of one or more buffer; (ii) a total of 0.2-1 w/v% of one or more acid; (iii) a total of 0.2-2.0 w/v% of one or more resuspension aid; (iv) a total of 0.2 w/v% of one or more surfactant for wetting; (v) a total of 0.1 -3 w/v% of one or more preservative; (vi) a total of 1 w/w% of one or more surfactant; (vii) a total of 0.2-2.0 w/v% of one or more thickener; (viii) one or more additive for pH adjustment; and/or (ix) one or more palatant and/or flavoring agent.
  • the one or more buffer may comprise a phosphate buffer and/or a tris(hydroxymethyl)aminomethane (Tris) buffer
  • the one or more acid may comprise citric acid, citric acid monohydrate, or sorbic acid
  • the one or more resuspension aid may comprise microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more surfactant for wetting may comprise ethylene oxide/propylene oxide copolymer
  • the one or more preservative may comprise methylparaben, propylparaben, n-butyl alcohol, butylated hydroxytoluene (BHT), or a mixture thereof
  • the one or more surfactant may comprise glyceryl dibehenate
  • the one or more thickener may comprise microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more additive may comprise sodium hydroxide
  • the GC stimulator may have an enantiomeric purity of at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least
  • SUBSTITUTE SHEET (RULE 26) about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100%.
  • the enantiomeric purity is measured by High-Performance Liquid Chromatography (HPLC) and/or Ultra-High-Performance Liquid Chromatography (UHPLC).
  • the GC stimulator may comprise at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the S enantiomer.
  • the GC stimulator may comprise at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the R enantiomer.
  • At least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the GC stimulator may be maintained in a solid state in the oral suspension.
  • the solid state GC stimulator may remain stable in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C for at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years with non-significant degradation observed.
  • At least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of the solid state GC stimulator may remain stable.
  • stability may be measured via % or area %.
  • the solid state GC stimulator may have a half life in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator may have a half life in oral suspension after
  • SUBSTITUTE SHEET (RULE 26) and/or while under exposure to UV/VIS radiation of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator may remain stable in the oral suspension after exposure to UV and/or VIS radiation with a light intensity of about 200 Wh/m2 for about 24 hours with non-significant degradation observed.
  • at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the solid state GC stimulator may remain non-degraded.
  • degradation may be measured via % or area %.
  • the GC stimulator may be capable of remaining stable after dissolving in an aqueous solvent for at least about 1 week under room temperature, or dissolving in an HCI solution of about 0.1 M for at least about 1 week under room temperature, or dissolving in a buffer with a pH value of about 10 for at least about 1 week under room temperature, or dissolving in a phosphate buffer with a pH value of about 7 for at least about 1 week under room temperature, with non-significant hydrolysis observed.
  • a method of treating hypertension and/or associated diseases comprising: administering to a subject in need thereof a pharmaceutical formulation comprising a therapeutically effective amount of one or more guanylate cyclase (GC) stimulator described herein.
  • GC guanylate cyclase
  • the pharmaceutical formulation comprising the therapeutically effective amount of the GC stimulator may be administered by oral route, an intravenous route, a parenteral route, and/or a topical route.
  • a method of treating and/or preventing hypertension and/or associated diseases comprising: administering to a subject in need thereof the pharmaceutical formulation comprising a therapeutically effective amount of one or more guanylate cyclase (GC) stimulator in oral suspension described herein.
  • GC guanylate cyclase
  • a method of treating and/or preventing hypertension and/or associated diseases comprising: orally administering to a subject a pharmaceutically acceptable oral suspension, wherein the oral suspension comprises: a guanylate cyclase (GC) stimulator, wherein the guanylate cyclase (GC) stimulator is a compound of Formula (I) or pharmaceutically acceptable salt thereof; and may optionally comprise: (i) a total of between about 0.01 and about 10 w/v%, between about 0.1 and about 9 w/v%, between about 0.25 and about 8 w/v%, between about 0.5 and about 7 w/v%, between about 0.75 and about 6 w/v%, between about 1 .0 and about 5 w/v%, between about 1 .25 and about 4 w/v%, between about 1 .5 and about 3 w/v%, or between about 0.1 and about 2 w/v
  • SUBSTITUTE SHEET (RULE 26) and about 5 w/v%, between about 0.2 and about 4 w/v%, between about 0.3 and about 3 w/v%, between about 0.4 and about 2.7 w/v%, between about 0.5 and about 2.6 w/v%, between about 0.6 and about 2.5 w/v%, between about 0.7 and about 2.4 w/v%, between about 0.8 and about 2.3 w/v%, between about 0.9 and about 2.2 w/v%, between about 1 .0 and about 2.1 w/v%, between about 1.1 and about 2.0 w/v%, between about 1 .2 and about 1 .9 w/v%, between about 1 .3 and about 1 .8 w/v%, between about 1 .4 and about 1 .7 w/v%, or between about 1 .5 and about 1.6 w/v% of one or more preservative; (vi) a total of between about 0.01 and about 5 w/
  • the oral suspension may comprise: (i) a total of 0.1-2 w/v% of one or more buffer; (ii) a total of 0.2-1 w/v% of one or more acid; (iii) a total of 0.2- 2.0 w/v% of one or more resuspension aid; (iv) a total of 0.2 w/v% of one or more surfactant for wetting; (v) a total of 0.1 -3 w/v% of one or more preservative; (vi) a total of 1 w/w% of one or more surfactant; (vii) a total of 0.2-2.0 w/v% of one or more thickener; (viii) - 9 -
  • SUBSTITUTE SHEET (RULE 26) one or more additive for pH adjustment; and/or (ix) one or more palatant and/or flavoring agent.
  • the one or more buffer may comprise a phosphate buffer and/or a tris(hydroxymethyl)aminomethane (Tris) buffer
  • the one or more acid may comprise citric acid, citric acid monohydrate, or sorbic acid
  • the one or more resuspension aid may comprise microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more surfactant for wetting may comprise ethylene oxide/propylene oxide copolymer
  • the one or more preservative may comprise methylparaben, propylparaben, n-butyl alcohol, butylated hydroxytoluene (BHT), or a mixture thereof
  • the one or more surfactant may comprise glyceryl dibehenate
  • the one or more thickener may comprise microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more additive may comprise sodium hydroxide
  • the oral suspension may have a pH value of between about 4.6 and about 9.4, between about 4.7 to 9.3, between about 4.8 and about 9.2, between about 4.9 and about 9.1 , between about 5.0 and about 9.0, between about 5.1 and about 8.9, between about 5.3 and about 8.8, between about 5.4 and about 8.7, between about 5.5 and about 8.6, between about 5.6 and about 8.5, between about 5.7 and about 8.4, between about 5.8 and about 8.3, between about 5.9 and about 8.2, between about 6.0 and about 8.1 , between about 6.1 and about 8.0, between about 6.0 and about 7.9, between about 6.1 and about 7.8, between about 6.2 and about 7.7, between about 6.3 and about 7.7, between about 6.4 and about 7.6, between 6.5 and about 7.5, between about 6.6 and about 7.4, between about 6.7 and about 7.3, between about 6.8 and about 7.2, between about 6.9 and about 7.1 , between about 4.6 and about 8.3, between about 4.7 and about 8.
  • SUBSTITUTE SHEET (RULE 26) Q.7 and about 7.8, between about 6.8 and about 7.7, between about 6.8 and about 7.6, between about 6.8 and about 7.5, between about 6.8 and about 7.4, between about 6.8 and about 7.3, between about 6.9 and about 7.2, between about 6.9 to 7.1 , greater than about 4.5 but less than about 8.1 , greater than about 5.0 but less than about 8.1 , greater than about 5.5 but less than about 8.1 , greater than about 6.0 but less than about 8.1 , greater than about 6.1 but less than about 8.1 , greater than about 6.2 but less than about 8.1 , greater than about 6.3 but less than about 8.1 , greater than about 6.4 but less than about 8.1 , greater than about 6.5 but less than about 8.1 , greater than about 6.6 but less than about 8.1 , greater than about 6.7 but less than about 8.1 , greater than about 6.8 but less than about 8.1 , greater than about 6.9 but less than about 8.1 , greater than about 7.0
  • the oral suspension may comprise between about 0.1 and about 2 w/v%, between about 0.25 and about 1 .75 w/v%, between about 0.5 and about 1.5 w/v%, between about 1 and about 1 .25 w/v%, about 0.1 w/v%, about 0.25 w/v%, about 0.5 w/v%, about 0.75 w/v%, about 1 w/v%, about 1 .5 w/v%, about 1 .75 w/v%, or about 2 w/v% of the GC stimulator.
  • At least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the GC stimulator may be maintained in a solid state in the oral suspension.
  • the subject in need thereof may be a vertebrate.
  • the subject may be feline, canine, or equine.
  • the hypertension and/or associated diseases may be one or more selected from hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, disturbances of atrial and ventricular rhythm and conduction disturbances, for example atrioventricular blocks of degree l-lll (AVB l-lll), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsade-de-pointes tachycardia, atrial and ventricular extrasystoles, AV junction extrasystoles, sick-sinus syndrome, syncopes, AV-
  • treating the hypertension and/or associated diseases may comprise decreasing or substantially decreasing a mean arterial blood pressure, a systolic blood pressure, and/or a diastolic blood pressure.
  • treating the hypertension and/or associated diseases may comprise decreasing a mean arterial blood pressure, a systolic blood pressure, and/or a diastolic blood pressure to about, to within about 1 %, to within about 2%, to within about 3%, to within about 4%, to within about 5%, to within about 10%, to within about 15%, or to within about 20% the blood pressure considered normal for the species treated.
  • the plasma concentration of the GC stimulator in the subject may be higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18 pg/L, about 19 pg/L, or about 20 pg/L about 24 hours after administration of the oral suspension.
  • the plasma concentration of the GC stimulator in the subject may be higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18 pg/L, about 19 pg/L, or about 20 pg/L about 48 hours after administration of the oral suspension.
  • the plasma concentration of the GC stimulator in the subject may be higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18 pg/L, about 19 pg/L, or about 20 pg/L about 60 hours after administration of the oral suspension.
  • a dose of the GC stimulator administered to the subject may be about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg about 1 mg/kg, about 1 .25 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, or about 2 mg/kg.
  • a dose of the GC stimulator may be administered to the subject four times per day, three times per day, twice per day, once per day, once per two days, once per week, once per month, once per two months, or once per three months.
  • the pharmaceutical formulation or oral suspension may be voluntarily consumed by the subject.
  • the GC stimulator may be administered to the subject in combination with one or more of a second GC stimulator and/or an additional therapeutic agent.
  • the additional therapeutic agent may be selected from (i) one or more organic nitrate and/or NO donor, optionally selected from sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 , or inhalational NO; (ii) one or more compound that inhibits the degradation of cyclic guanosine monophosphate (cGMP), optionally selected from inhibitors of phosphodiesterases (PDE) 1 , 2 and/or 5, optionally PDE-5 inhibitors, optionally sildenafil, vardenafil, or tadalafil; (iii) one or more antithrombotic agent, optionally selected from platelet aggregation inhibitors, optionally aspir
  • cGMP cyclic guanosine monophosphate
  • PDE phospho
  • a method of forming a pharmaceutically acceptable oral suspension comprising a guanylate cyclase (GC) stimulator, wherein the a guanylate cyclase (GC) stimulator is a compound of Formula (I)
  • a pharmaceutically acceptable salt thereof may be provided, the method comprising: mixing the GC of Formula (I) or pharmaceutically acceptable salt thereof with an aqueous or oily solution; and adjusting the pH value to between about 5 and about 14 to form the oral suspension with the GC stimulator dispersed in the solution as insoluble solid particles.
  • the pH may be adjusted such that at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the GC stimulator is maintained in a solid state in the oral suspension.
  • the pH may be adjusted to between about 4.6 and about 9.4, between about 4.7 to 9.3, between about 4.8 and about 9.2, between about 4.9 and about 9.1 , between about 5.0 and about 9.0, between about 5.1 and about 8.9, between about 5.3 and about 8.8, between about 5.4 and about 8.7, between about 5.5 and about 8.6, between about 5.6 and about 8.5, between about 5.7 and about 8.4, between about 5.8 and about 8.3, between about 5.9 and about 8.2, between about 6.0 and about 8.1 , between about 6.1 and about 8.0, between about 6.0 and about 7.9, between about 6.1 and about 7.8, between about 6.2 and about 7.7, between about 6.3 and about 7.7, between about 6.4 and about 7.6, between 6.5 and about 7.5, between about 6.6 and about 7.4, between about 6.7 and about 7.3, between about 6.8 and about 7.2, between about 6.9 and about 7.1 , between about 4.6 and about 8.3, between about 4.7 and about 8.
  • SUBSTITUTE SHEET (RULE 26) about 6.1 and about 8.0, between about 6.4 and about 8.0, between about 6.5 and about 8.0, between about 6.6 and about 7.9, between about 6.7 and about 7.8, between about
  • the method may further comprise adding (i) a total of between about 0.01 and about 10 w/v%, between about 0.1 and about 9 w/v%, between about 0.25 and about 8 w/v%, between about 0.5 and about 7 w/v%, between about 0.75 and about 6 w/v%, between about 1 .0 and about 5 w/v%, between about 1 .25 and about 4 w/v%, between about 1 .5 and about 3 w/v%, or between about 0.1 and about 2 w/v% of one or more buffer; (ii) a total of between about 0.01 and about 5 w/v%, between about 0.05 and about 4 w/v%, between about 0.075 and about 3 w/v%, between about 0.1 and about 2 w/v%, between about 0.125 and about 1 w/v%, between about 0.15 and about 0.75 w/v%, or between about 0.2 and about 0.5 w/v% of one or more buffer; (ii)
  • SUBSTITUTE SHEET (RULE 26) w/v%, between about 0.075 and about 2 w/v%, between 0.1 and about 1 w/v%, between about 0.005 and about 0.2 w/v%, between about 0.05 and about 0.1 w/v%, between about 0.1 and about 0.125 w/v%, between about 0.1 and about 0.15, or between about 0.1 and about 0.175 w/v% of one or more surfactant for wetting; (v) a total of between about 0.1 and about 5 w/v%, between about 0.2 and about 4 w/v%, between about 0.3 and about 3 w/v%, between about 0.4 and about 2.7 w/v%, between about 0.5 and about 2.6 w/v%, between about 0.6 and about 2.5 w/v%, between about 0.7 and about 2.4 w/v%, between about 0.8 and about 2.3 w/v%, between about 0.9 and about 2.2 w/v%, between about 1
  • the method may further comprise adding: (i) a total of 0.1-2 w/v% of one or more buffer; (ii) a total of 0.2-1 w/v% of one or more acid; (iii) a total of 0.2-2.0 w/v% of one or more resuspension aid; (iv) a total of 0.2 w/v% of one or more surfactant for wetting; (v) a total of 0.1 -3 w/v% of one or more preservative; (vi) a total of 1 w/w% of one or more surfactant; (vii) a total of 0.2-2.0 w/v% of one or more thickener; (viii) one or more additive for pH adjustment; and/or (ix) one or more palatant and/or flavoring agent.
  • the one or more buffer may comprise a phosphate buffer and/or a tris(hydroxymethyl)aminomethane (Tris) buffer
  • the one or more acid may comprise citric acid, citric acid monohydrate, or sorbic acid
  • the one or more resuspension aid may comprise microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more surfactant for wetting may comprise ethylene oxide/propylene oxide copolymer
  • the one or more preservative may comprise methylparaben, propylparaben, n-butyl alcohol, butylated hydroxytoluene (BHT), or a mixture thereof
  • the one or more surfactant may comprise glyceryl dibehenate
  • the one or more thickener may comprise microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more additive may comprise sodium hydroxide
  • the oral suspension may comprise between about 0.1 and about 2 w/v%, between about 0.25 and about 1 .75 w/v%, between about 0.5 and about 1.5 w/v%, between about 1 and about 1 .25 w/v%, about 0.1 w/v%, about 0.25 w/v%, about 0.5 w/v%, about 0.75 w/v%, about 1 w/v%, about 1 .5 w/v%, about 1 .75 w/v%, or about 2 w/v% of the GC stimulator.
  • the GC stimulator may have an enantiomeric purity of at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100%.
  • the enantiomeric purity may be measured by High-Performance Liquid Chromatography (HPLC) and/or Ultra-High-Performance Liquid Chromatography (UHPLC).
  • the GC stimulator may comprise at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the S enantiomer.
  • the GC stimulator may comprise at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the R enantiomer.
  • the solid state GC stimulator may remain stable in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C for at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, or at least about one year with non-significant degradation observed.
  • At least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of the solid state GC stimulator may remain stable.
  • stability may be measured via % or area %.
  • the solid state GC stimulator may have a half life in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator may have a half life in oral suspension after and/or while under exposure to UV/VIS radiation of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator may remain stable in the oral suspension after exposure to UV and/or VIS radiation with a light intensity of about 200 Wh/m2 for about 24 hours with non-significant degradation observed. In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at
  • SUBSTITUTE SHEET (RULE 26) least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the solid state GC stimulator may remain non-degraded. In some embodiments, degradation may be measured via % or area %.
  • the GC stimulator may be capable of remaining stable after dissolving in an aqueous solvent for at least about 1 week under room temperature, or dissolving in an HCI solution of about 0.1 M for at least about 1 week under room temperature, or dissolving in a buffer with a pH value of about 10 for at least about 1 week under room temperature, or dissolving in a phosphate buffer with a pH value of about 7 for at least about 1 week under room temperature, with non-significant hydrolysis observed.
  • At least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the solid state GC stimulator may remain stable.
  • a therapeutically effective amount of pharmaceutical formulation comprising a guanylate cyclase (GC) stimulator, wherein the guanylate cyclase (GC) stimulator is a compound of Formula (I) or a pharmaceutically acceptable salt thereof; for use to treat and/or prevent hypertension and/or associated diseases in a subject in need thereof may be provided.
  • a guanylate cyclase (GC) stimulator is a compound of Formula (I) or a pharmaceutically acceptable salt thereof
  • the guanylate cyclase (GC) stimulator may be formulated as an oral suspension, an oral solution, a solution suitable for intravenous and/or parenteral administration, or a topical medication.
  • the pharmaceutical formulation may be an oral suspension.
  • the pharmaceutical formulation may be an oral suspension that is water-based or oil-based.
  • the oral suspension may have a pH value of between about 4.6 and about 9.4, between about 4.7 to 9.3, between about 4.8 and about 9.2, between about 4.9 and about 9.1 , between about 5.0 and about 9.0, between about 5.1 and about 8.9, between about 5.3 and about 8.8, between about 5.4 and about 8.7, between about 5.5 and about 8.6, between about 5.6 and about 8.5, between about 5.7 and about 8.4, between about 5.8 and about 8.3, between about 5.9 and about 8.2, between about 6.0 and about 8.1 , between about 6.1 and about 8.0, between about 6.0 and about 7.9, between about 6.1 and about 7.8, between about 6.2 and about 7.7, between about 6.3 and about 7.7, between about 6.4 and about 7.6, between 6.5 and about 7.5, between about 6.6 and about 7.4, between about 6.7 and about 7.3, between about 6.8 and about 7.2, between about 6.9 and about 7.1 , between about 4.6 and about 8.3, between
  • the pharmaceutical formulation may comprise between about 0.1 and about 2 w/v%, between about 0.25 and about 1 .75 w/v%, between about 0.5
  • SUBSTITUTE SHEET (RULE 26) and about 1 .5 w/v%, between about 1 and about 1 .25 w/v%, about 0.1 w/v%, about 0.25 w/v%, about 0.5 w/v%, about 0.75 w/v%, about 1 w/v%, about 1 .5 w/v%, about 1 .75 w/v%, or about 2 w/v% of the GC stimulator.
  • the pharmaceutical formulation may further comprise: (i) a total of between about 0.01 and about 10 w/v%, between about 0.1 and about 9 w/v%, between about 0.25 and about 8 w/v%, between about 0.5 and about 7 w/v%, between about 0.75 and about 6 w/v%, between about 1 .0 and about 5 w/v%, between about 1 .25 and about 4 w/v%, between about 1 .5 and about 3 w/v%, or between about 0.1 and about 2 w/v% of one or more buffer; (ii) a total of between about 0.01 and about 5 w/v%, between about 0.05 and about 4 w/v%, between about 0.075 and about 3 w/v%, between about 0.1 and about 2 w/v%, between about 0.125 and about 1 w/v%, between about 0.15 and about 0.75 w/v%, or between about 0.2 and about 0.5 w/v% of
  • SUBSTITUTE SHEET (RULE 26) between about 0.05 and about 0.1 w/v%, between about 0.1 and about 0.125 w/v%, between about 0.1 and about 0.15, or between about 0.1 and about 0.175 w/v% of one or more surfactant; (vii) a total of between about 0.01 and about 5 w/v%, between about 0.25 and about 4 w/v%, between about 0.5 and about 3 w/v%, between about 0.75 and about 2 w/v%, between about 1 and about 1.75 w/v%, between about 0.15 and about 1.5 w/v%, between about 0.2 and about 2.0 w/v%, between about 0.3 and about 1 .9 w/v%, between about 0.4 and about 1 .8 w/v%, between about 0.5 and about 1.7 w/v%, between about 0.6 and about 1 .6 w/v%, between about 0.7 and aboutl .5 w/v%, between about 0.8 and about
  • the pharmaceutical formulation may comprises: (i) a total of 0.1-2 w/v% of one or more buffer; (ii) a total of 0.2-1 w/v% of one or more acid; (iii) a total of 0.2-2.0 w/v% of one or more resuspension aid; (iv) a total of 0.2 w/v% of one or more surfactant for wetting; (v) a total of 0.1 -3 w/v% of one or more preservative; (vi) a total of 1 w/w% of one or more surfactant; (vii) a total of 0.2-2.0 w/v% of one or more thickener; (viii) one or more additive for pH adjustment; and/or (ix) one or more palatant and/or flavoring agent.
  • the one or more buffer may comprise a phosphate buffer and/or a tris(hydroxymethyl)aminomethane (Tris) buffer
  • the one or more acid may comprise citric acid, citric acid monohydrate, or sorbic acid
  • the one or more resuspension aid may comprise microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more surfactant for wetting may comprise ethylene oxide/propylene oxide copolymer
  • the one or more preservative may comprise methylparaben, propylparaben, n-butyl alcohol, butylated hydroxytoluene (BHT), or a mixture thereof
  • the one or more surfactant may comprise glyceryl dibehenate
  • the one or more surfactant may comprise glyceryl dibehenate
  • one or more thickener may comprise microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more additive may comprise sodium hydroxide, hydrochloric acid, or a mixture thereof
  • the one or more palatant and/or flavoring agent may comprise one or more vanilla flavoring, one or more cheese flavoring, one or more fish flavoring, one or more chicken flavoring, one or more pork flavoring, and/or one or more beef flavoring.
  • the phosphate buffer may comprise a dibasic sodium phosphate.
  • the GC stimulator may have an enantiomeric purity of at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100%.
  • the enantiomeric purity may be measured by High-Performance Liquid Chromatography (HPLC) and/or Ultra-High-Performance Liquid Chromatography (UHPLC).
  • the GC stimulator may comprise at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the S enantiomer.
  • the GC stimulator may comprise at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the R enantiomer.
  • At least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the GC stimulator may be maintained in a solid state in the oral suspension.
  • the solid state GC stimulator may remain stable in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C for at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, or at least about one year with non-significant degradation
  • SUBSTITUTE SHEET (RULE 26) observed.
  • at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of the solid state GC stimulator may remain stable.
  • stability may be measured via % or area %.
  • the solid state GC stimulator may have a half life in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator may have a half life in oral suspension after and/or while under exposure to UV and/or VIS radiation of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator may remain stable in the oral suspension after exposure to UV and/or VIS radiation with a light intensity of about 200 Wh/m2 for about 24 hours with non-significant degradation observed.
  • at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the solid state GC stimulator may remain non-degraded.
  • degradation may be measured via % or area %.
  • the GC stimulator may be capable of remaining stable after dissolving in an aqueous solvent for at least about 1 week under room temperature, or dissolving in an HCI solution of about 0.1 M for at least about 1 week under room temperature, or dissolving in a buffer with a pH value of about 10 for at least about 1 week under room temperature, or dissolving in a phosphate buffer with a pH value of about 7 for at least about 1 week under room temperature, with non-significant hydrolysis observed.
  • At least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the solid state GC stimulator may remain stable.
  • the therapeutically effective amount of the GC stimulator may be formulated for administration by an oral route, an intravenous route, a parenteral route, and/or a topical route.
  • the subject in need thereof may be a vertebrate.
  • the subject may be feline, canine, or equine.
  • the hypertension and/or associated diseases may be one or more selected from hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, disturbances of atrial and ventricular rhythm and conduction disturbances, for example atrioventricular blocks of degree l-lll (AVB l-lll), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsade-de-pointes tachycardia, atrial and ventricular extrasystoles, AV junction extrasystoles, sick-sinus syndrome, syncopes, AV- node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvulitis,
  • treating the hypertension and/or associated diseases may comprise decreasing or substantially decreasing a mean arterial blood pressure, a systolic blood pressure, and/or a diastolic blood pressure.
  • treating the hypertension and/or associated diseases may comprise decreasing a mean arterial blood pressure, a systolic blood pressure, and/or a diastolic blood pressure to about, to within about 1 %, to within about 2%, to within about 3%, to within about 4%, to within about 5%, to within about 10%, to within about 15%, or to within about 20% the blood pressure considered normal for the species treated.
  • the pharmaceutical formulation may be formulated such that the plasma concentration of the GC stimulator in the subject is higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18 pg/L, about 19 pg/L, or about 20 pg/L about 24 hours after administration of the oral suspension.
  • the pharmaceutical formulation may formulated such that plasma concentration of the GC stimulator in the subject is higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18
  • SUBSTITUTE SHEET (RULE 26) pg/L, about 19 pg/L, or about 20 pg/L about 48 hours after administration of the oral suspension.
  • the pharmaceutical formulation may be formulated such that plasma concentration of the GC stimulator in the subject is higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18 pg/L, about 19 pg/L, or about 20 pg/L about 60 hours after administration of the oral suspension.
  • a dose of the GC stimulator may be formulated for administration to the subject at a dosage of about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg about 1 mg/kg, about 1 .25 mg/kg, about 1 .5 mg/kg, about 1.75 mg/kg, or about 2 mg/kg.
  • a dose of the GC stimulator may be formulated for administration to the subject four times per day, three times per day, twice per day, once per day, once per two days, once per week, once per month, once per two months, or once per three months.
  • the GC stimulator may be formulated such that it is voluntarily consumed by the subject.
  • the GC stimulator may be formulated for administration to the subject in combination with one or more of a second GC stimulator and/or an additional therapeutic agent.
  • the additional therapeutic agent may be selected from (i) one or more organic nitrate and/or NO donor, optionally selected from sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 , or inhalational NO; (ii) one or more compound that inhibits the degradation of cyclic guanosine monophosphate (cGMP), optionally selected from inhibitors of phosphodiesterases (PDE) 1 , 2 and/or 5, optionally PDE-5 inhibitors, optionally sildenafil, vardenafil, or tadalafil; (iii) one or more antithrombotic agent, optionally selected from platelet aggregation inhibitors, optionally aspirin, clopidogrel, ticlopidine or dipyridamole; anticoagulants; thrombin inhibitors, optionally ximelagatran, dabigatran, melagatran
  • SUBSTITUTE SHEET (RULE 26) endothelin antagonists; renin inhibitors; alpha-blockers; beta-blockers, optionally propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol; mineralocorticoid receptor antagonists; or diuretics; (v) one or more active substance that alters fat metabolism, optional
  • FIG. 1 is an exemplary chart showing the plasma concentration of GC stimulator of Formula (I) after administering formulations comprising GC stimulator of Formula (I) to cats.
  • FIG. 2 is an exemplary chart showing the plasma concentration of GC stimulator of Formula (I) after administering formulations comprising GC stimulator of Formula (I) to cats.
  • FIG. 3 is an exemplary chart showing the plasma concentration of GC stimulator of Formula (I) after administering formulations comprising GC stimulator of Formula (I) to cats.
  • Fig. 4 is a flow chart illustrating the blood pressure measurement plan of Example 8.
  • GC stimulators may be very sensitive to UV and/or VIS radiation or susceptible to hydrolysis.
  • the subject being treated may be unwilling to take the medicine voluntarily due to an unpleasant taste.
  • the compounds of the present invention include Guanylate Cyclase (GC) Stimulators having Formula (I):
  • the compounds of the present invention include Guanylate Cyclase (GC) Stimulators having the chemical name N-(2-amino-5,5,5-trifluoro-2-methylpentyl)-8-[(2,6- difluorobenzyl)oxy]-2,6-dimethylimidazo[1 ,2-a]pyridine-3-carboxamide.
  • GC Guanylate Cyclase
  • the compounds of the present disclosure also include pharmaceutically acceptable salts of the compounds disclosed herein.
  • pharmaceutically acceptable salt refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a compound disclosed herein.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • salts include, but are not limited to, those derived from organic and inorganic acids such as, but not limited to, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing
  • the GC stimulator of the present disclosure has an enantiomeric purity of at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100%.
  • the enantiomeric purity is measured by High-Performance Liquid Chromatography (HPLC) and/or Ultra-High-Performance Liquid Chromatography (UHPLC).
  • the GC stimulator of the present disclosure comprises at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the S enantiomer.
  • the GC stimulator of the present disclosure comprises at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the R enantiomer.
  • the GC stimulator remains stable after dissolving in an aqueous solvent for at least about 1 week under room temperature, or dissolving in an HCI solution of about 0.1 M for at least about 1 week under room temperature, or dissolving in a buffer with a pH value of about 10 for at least about 1 week under room temperature, or dissolving in a phosphate buffer with a pH value of about 7 for at least about 1 week under room temperature, with non-significant hydrolysis observed.
  • the GC stimulators of the present disclosure may be synthesized by known methods of chemical synthesis. In some embodiments, GC stimulators of the present disclosure are synthesized using methods set forth in US Patent No. 10,052,312, which is incorporated by reference in its entirety. In some embodiments, GC stimulators of the present disclosure are synthesized using methods set forth in US Patent Application Publication No. US 2015/0274719, which is incorporated by reference in its entirety.
  • a method of forming a pharmaceutically acceptable oral suspension comprising a guanylate cyclase (GC) stimulator, wherein the a guanylate cyclase (GC) stimulator is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, is provided, the method comprising: (i) mixing the GC of Formula (I) or pharmaceutically acceptable salt thereof with an aqueous or oily solution; and (ii) adjusting the pH value to between about 5 and about 14 to form the oral suspension with the GC stimulator dispersed in the solution as insoluble solid particles.
  • a guanylate cyclase (GC) stimulator is a compound of Formula (I) or a pharmaceutically acceptable salt thereof
  • the method comprising: (i) mixing the GC of Formula (I) or pharmaceutically acceptable salt thereof with an aqueous or oily solution; and (ii) adjusting the pH value to between about 5 and about 14 to form the oral suspension with the GC stimulator dispersed in the solution as insoluble
  • the pH is adjusted such that at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the GC stimulator is maintained in a solid state in the oral suspension.
  • the pH is adjusted to between about 4.6 and about 9.4, between about 4.7 to 9.3, between about 4.8 and about 9.2, between about 4.9 and about 9.1 , between about 5.0 and about 9.0, between about 5.1 and about 8.9, between about
  • SUBSTITUTE SHEET (RULE 26) 5.3 and about 8.8, between about 5.4 and about 8.7, between about 5.5 and about 8.6, between about 5.6 and about 8.5, between about 5.7 and about 8.4, between about 5.8 and about 8.3, between about 5.9 and about 8.2, between about 6.0 and about 8.1 , between about 6.1 and about 8.0, between about 6.0 and about 7.9, between about 6.1 and about 7.8, between about 6.2 and about 7.7, between about 6.3 and about 7.7, between about 6.4 and about 7.6, between 6.5 and about 7.5, between about 6.6 and about 7.4, between about 6.7 and about 7.3, between about 6.8 and about 7.2, between about 6.9 and about 7.1 , between about 4.6 and about 8.3, between about 4.7 and about 8.
  • the method further comprises adding (i) a total of between about 0.01 and about 10 w/v%, between about 0.1 and about 9 w/v%, between about 0.25 and about 8 w/v%, between about 0.5 and about 7 w/v%, between about 0.75 and about 6 w/v%, between about 1 .0 and about 5 w/v%, between about 1 .25 and about 4 w/v%, between about 1 .5 and about 3 w/v%, or between about 0.1 and about 2 w/v% of
  • SUBSTITUTE SHEET (RULE 26) one or more buffer; (ii) a total of between about 0.01 and about 5 w/v%, between about 0.05 and about 4 w/v%, between about 0.075 and about 3 w/v%, between about 0.1 and about 2 w/v%, between about 0.125 and about 1 w/v%, between about 0.15 and about 0.75 w/v%, or between about 0.2 and about 0.5 w/v% of one or more acid; (iii) a total of between about 0.01 and about 5 w/v%, between about 0.25 and about 4 w/v%, between about 0.5 and about 3 w/v%, between about 0.75 and about 2 w/v%, between about 1 and about 1 .75 w/v%, between about 0.15 and about 1 .5 w/v%, between about 0.2 and about 2.0 w/v%, between about 0.3 and about 1 .9 w/v%, between about 0.4 and about 1
  • SUBSTITUTE SHEET (RULE 26) and about 1 .3 w/v%, between about 0.8 and about 1.2 w/v%, or between about 0.9 and about 1.1 w/v% of one or more thickener; (viii) a total of between about 0.05 and about 10 w/v%, between about 0.1 and about 9 w/v%, between about 0.25 and about 8 w/v%, between about 0.5 and about 7 w/v%, between about 0.75 and about 6 w/v%, between about 1.0 and about 5 w/v%, between about 1 .25 and about 4 w/v%, between about 1 .5 and about 3 w/v%, or between about 0.1 and about 2 w/v% of one or more additive for pH adjustment; and/or (ix) a total of between about 0.01 and about 5 w/v%, between about 0.01 and about 4 w/v%, between about 0.05 and about 3 w/v%, between about 0.075 and about
  • the method further comprises adding: (i) a total of 0.1-2 w/v% of one or more buffer; (ii) a total of 0.2-1 w/v% of one or more acid; (iii) a total of 0.2- 2.0 w/v% of one or more resuspension aid; (iv) a total of 0.2 w/v% of one or more surfactant for wetting; (v) a total of 0.1 -3 w/v% of one or more preservative; (vi) a total of 1 w/w% of one or more surfactant; (vii) a total of 0.2-2.0 w/v% of one or more thickener; (viii) one or more additive for pH adjustment; and/or (ix) one or more palatant and/or flavoring agent.
  • the one or more buffer comprises a phosphate buffer and/or a tris(hydroxymethyl)aminomethane (Tris) buffer
  • the one or more acid comprises citric acid, citric acid monohydrate, or sorbic acid
  • the one or more resuspension aid comprises microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more surfactant for wetting comprises ethylene oxide/propylene oxide copolymer
  • the one or more preservative comprises methylparaben, propylparaben, n-butyl alcohol, butylated hydroxytoluene (BHT), or a mixture thereof
  • the one or more surfactant comprises glyceryl dibehenate
  • the one or more thickener comprises microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more additive comprises sodium hydroxide, hydrochloric acid, or a mixture thereof
  • the phosphate buffer if present, comprises a dibasic sodium phosphate.
  • the oral suspension comprises between about 0.1 and about 2 w/v%, between about 0.25 and about 1 .75 w/v%, between about 0.5 and about 1 .5
  • SUBSTITUTE SHEET (RULE 26) w/v%, between about 1 and about 1 .25 w/v%, about 0.1 w/v%, about 0.25 w/v%, about 0.5 w/v%, about 0.75 w/v%, about 1 w/v%, about 1 .5 w/v%, about 1 .75 w/v%, or about 2 w/v% of the GC stimulator.
  • the GC stimulator has an enantiomeric purity of at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100%.
  • the enantiomeric purity is measured by High-Performance Liquid Chromatography (HPLC) and/or Ultra-High-Performance Liquid Chromatography (UHPLC).
  • the GC stimulator comprises at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the S enantiomer.
  • the GC stimulator comprises at least about 90%, at least about 93%, at least about 95%, at least about 98%, at least about 99%, at least about 99.1 %, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7, at least about 99.77%, at least about 99.8%, at least about 99.9%, or about 100% of the R enantiomer.
  • the solid state GC stimulator remains stable in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C for at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years with nonsignificant degradation observed.
  • At least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of the solid state GC stimulator remains stable.
  • the stability is measured by any suitable method such as known methods. In some embodiments, stability is measured via % or area %.
  • the solid state GC stimulator may have a half life in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C of at least about one week, at least about one month, at least about two months, at least about three
  • SUBSTITUTE SHEET (RULE 26) months at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator has a half life in oral suspension after and/or while under exposure to UV/VIS radiation of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator remains stable in the oral suspension after exposure to UV and/or VIS radiation with a light intensity of about 200 Wh/m2 for about 24 hours with non-significant degradation observed.
  • the degradation is measured by any suitable method such as known methods.
  • degradation is measured via % or area %.
  • composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient(s) to be effective, and which contains no additional components that are unacceptably toxic to a subject to which the formulation would be administered.
  • “Pharmaceutically acceptable” may refer to a composition, component, or compound that is generally safe, that is non-toxic or has toxicity that is acceptable in consideration of any benefits conferred, and/or that is generally considered acceptable for veterinary and/or human pharmaceutical use. “Pharmaceutically acceptable” may refer to a composition, component, or compound that is approved for veterinary and/or human use by a regulatory agency, such as, but not limited to, the United States Food and Drug Administration, the European Medicines Agency, and/or other similar agency, and/or that is listed in the U.S. Pharmacopeia or other recognized pharmacopeia.
  • a regulatory agency such as, but not limited to, the United States Food and Drug Administration, the European Medicines Agency, and/or other similar agency, and/or that is listed in the U.S. Pharmacopeia or other recognized pharmacopeia.
  • a “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a “pharmaceutical composition” for administration to a subject.
  • a pharmaceutically acceptable carrier is non- toxic to recipients at the dosages and concentrations employed and is compatible with
  • SUBSTITUTE SHEET (RULE 26) other ingredients of the formulation.
  • the pharmaceutically acceptable carrier is appropriate for the formulation employed.
  • pharmaceutically acceptable carriers include alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin, canine, feline, equine or other animal albumin; buffers such as phosphate, citrate, tromethamine or HEPES buffers; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, or magnesium trisilicate; polyvinyl pyrrolidone, cellulose-based substances; polyethylene glycol; sucrose; mannitol; or amino acids including, but not limited to, arginine.
  • a “therapeutically effective amount” of a substance/molecule, agonist or antagonist may vary according to factors such as the type of disease to be treated, the disease state, the seventy and course of the disease, the type of therapeutic purpose, any previous therapy, the clinical history, the response to prior treatment, the discretion of the attending veterinarian, age, sex, and weight of the animal, and the ability of the substance/molecule, agonist or antagonist to elicit a desired response in the animal.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the substance/molecule, agonist or antagonist are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount may be delivered in one or more administrations.
  • a therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.
  • ICso means “half maximal inhibitory concentration,” which is the concentration of the test compound that is required to inhibit a biological process or biological component by 50% in vitro.
  • ECso means “half maximal effective concentration,” which is the concentration of the test compound that is required to obtain a 50% effect.
  • a pharmaceutical formulation for treating hypertension and/or associated diseases comprising: a therapeutically effective amount of a guanylate cyclase (GC) stimulator, wherein the GC stimulator is a compound of Formula (I):
  • GC guanylate cyclase
  • the pharmaceutical formulation is an oral suspension, an oral solution, a solution suitable for intravenous and/or parenteral administration, or a topical medication.
  • the pharmaceutical formulation is an oral suspension.
  • the oral suspension is water-based or oil-based.
  • the oral suspension has a pH value of between about 4.6 and about 9.4, between about 4.7 to 9.3, between about 4.8 and about 9.2, between about 4.9 and about 9.1 , between about 5.0 and about 9.0, between about 5.1 and about 8.9, between about 5.3 and about 8.8, between about 5.4 and about 8.7, between about 5.5 and about 8.6, between about 5.6 and about 8.5, between about 5.7 and about 8.4, between about 5.8 and about 8.3, between about 5.9 and about 8.2, between about 6.0 and about 8.1 , between about 6.1 and about 8.0, between about 6.0 and about 7.9, between about 6.1 and about 7.8, between about 6.2 and about 7.7, between about 6.3 and about 7.7, between about 6.4 and about 7.6, between 6.5 and about 7.5, between about 6.6 and about 7.4, between about 6.7 and about 7.3, between about 6.8 and about 7.2, between about 6.9 and about 7.1 , between about 4.6 and about 8.3, between about
  • SUBSTITUTE SHEET between about 6.9 and about 7.2, between about 6.9 to 7.1 , greater than about 4.5 but less than about 8.1 , greater than about 5.0 but less than about 8.1 , greater than about 5.5 but less than about 8.1 , greater than about 6.0 but less than about 8.1 , greater than about 6.1 but less than about 8.1 , greater than about 6.2 but less than about 8.1 , greater than about 6.3 but less than about 8.1 , greater than about 6.4 but less than about 8.1 , greater than about 6.5 but less than about 8.1 , greater than about 6.6 but less than about 8.1 , greater than about 6.7 but less than about 8.1 , greater than about 6.8 but less than about 8.1 , greater than about 6.9 but less than about 8.1 , greater than about 7.0 but less than about 8.1 , greater than about 7.1 but less than about 8.1 , greater than about 7.2 but less than about 8.1 , greater than about 7.3 but less than about 8.1 , greater than about 7.
  • the pharmaceutical formulation comprises between about 0.1 and about 2 w/v%, between about 0.25 and about 1 .75 w/v%, between about 0.5 and about 1 .5 w/v%, between about 1 and about 1 .25 w/v%, about 0.1 w/v%, about 0.25 w/v%, about 0.5 w/v%, about 0.75 w/v%, about 1 w/v%, about 1 .5 w/v%, about 1 .75 w/v%, or about 2 w/v% of the GC stimulator.
  • the pharmaceutical formulation further comprises: (i) a total of between about 0.01 and about 10 w/v%, between about 0.1 and about 9 w/v%, between about 0.25 and about 8 w/v%, between about 0.5 and about 7 w/v%, between about 0.75 and about 6 w/v%, between about 1 .0 and about 5 w/v%, between about 1 .25 and about 4 w/v%, between about 1 .5 and about 3 w/v%, or between about 0.1 and about 2 w/v% of one or more buffer; (ii) a total of between about 0.01 and about 5 w/v%, between about 0.05 and about 4 w/v%, between about 0.075 and about 3 w/v%, between about 0.1 and about 2 w/v%, between about 0.125 and about 1 w/v%, between about 0.15 and about 0.75 w/v%, or between about 0.2 and about 0.5 w/v% of one or more buffer; (ii)
  • SUBSTITUTE SHEET (RULE 26) 0.01 and about 5 w/v%, between about 0.01 and about 4 w/v%, between about 0.05 and about 3 w/v%, between about 0.075 and about 2 w/v%, between 0.1 and about 1 w/v%, between about 0.005 and about 0.2 w/v%, between about 0.05 and about 0.1 w/v%, between about 0.1 and about 0.125 w/v%, between about 0.1 and about 0.15, or between about 0.1 and about 0.175 w/v% of one or more surfactant for wetting; (v) a total of between about 0.1 and about 5 w/v%, between about 0.2 and about 4 w/v%, between about 0.3 and about 3 w/v%, between about 0.4 and about 2.7 w/v%, between about 0.5 and about 2.6 w/v%, between about 0.6 and about 2.5 w/v%, between about 0.7 and about
  • w/v% between about 0.8 and about 2.3 w/v%, between about 0.9 and about 2.2 w/v%, between about 1.0 and about 2.1 w/v%, between about 1.1 and about 2.0 w/v%, between about 1.2 and about 1 .9 w/v%, between about 1 .3 and about 1.8 w/v%, between about 1 .4 and about 1 .7 w/v%, or between about 1 .5 and about 1 .6 w/v% of one or more preservative; (vi) a total of between about 0.01 and about 5 w/v%, between about 0.01 and about 4 w/v%, between about 0.05 and about 3 w/v%, between about 0.075 and about 2 w/v%, between about 0.1 and about 1 w/v%, between about 0.01 and about 0.2 w/v%, between about 0.05 and about 0.1 w/v%, between about 0.1 and about 0.125 w/v%, between
  • the pharmaceutical formulation comprises: (i) a total of 0.1-2 w/v% of one or more buffer; (ii) a total of 0.2-1 w/v% of one or more acid; (iii) a total of 0.2-2.0 w/v% of one or more resuspension aid; (iv) a total of 0.2 w/v% of one or more surfactant for wetting; (v) a total of 0.1 -3 w/v% of one or more preservative; (vi) a total of 1 w/w% of one or more surfactant; (vii) a total of 0.2-2.0 w/v% of one or more thickener; (viii) one or more additive for pH adjustment; and/or (ix) one or more palatant and/or flavoring agent.
  • the one or more buffer comprises a phosphate buffer and/or a tris(hydroxymethyl)aminomethane (Tris) buffer
  • the one or more acid comprises citric acid, citric acid monohydrate, or sorbic acid
  • the one or more resuspension aid comprises microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more surfactant for wetting comprises ethylene oxide/propylene oxide copolymer
  • the one or more preservative comprises methylparaben, propylparaben, n-butyl alcohol, butylated hydroxytoluene (BHT), or a mixture thereof
  • the one or more surfactant comprises glyceryl dibehenate
  • the one or more thickener comprises microcrystalline cellulose and/or carboxymethylcellulose sodium
  • the one or more additive comprises sodium hydroxide, hydrochloric acid, or
  • the GC stimulator is maintained in a solid state in the oral suspension. In some embodiments, at least about 80%, at least about 85%, at least about 90%, at least about 91 %, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of the GC stimulator is maintained in a solid state in the oral suspension.
  • the solid state GC stimulator remains stable in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C for at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, or at least about one year with non-significant degradation observed.
  • SUBSTITUTE SHEET (RULE 26) least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% of the solid state GC stimulator remains stable.
  • stability is measured by any suitable method, such as known methods. In some embodiments, stability is measured via % or area %.
  • the solid state GC stimulator has a half life in oral suspension at about 25°C, about 30°C, about 35°C, about 40°C, or about 45°C of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator has a half life in oral suspension after and/or while under exposure to UV/VIS radiation of at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about five months, at least about six months, at least about nine months, at least about one year, or at least about two years.
  • the solid state GC stimulator remains stable in oral suspension after exposure to UV and/or VIS radiation with a light intensity of about 200 Wh/m2 for about 24 hours with non-significant degradation observed.
  • degradation is measured by any suitable method, such as known methods.
  • degradation is measured via % or area %.
  • a method of treating hypertension and/or associated diseases comprising administering to a subject in need thereof a pharmaceutical formulation comprising a therapeutically effective amount of a guanylate cyclase (GC) described herein is provided.
  • a pharmaceutical formulation comprising a therapeutically effective amount of a guanylate cyclase (GC) described herein is provided.
  • GC guanylate cyclase
  • the pharmaceutical formulation comprising the therapeutically effective amount of the GC stimulator is administered by oral route, an intravenous route, a parenteral route, and/or a topical route.
  • a method of treating and/or preventing hypertension and/or associated diseases comprising administering to a subject in need thereof the pharmaceutical formulation comprising a therapeutically effective amount of the guanylate cyclase (GC) stimulator in oral suspension described herein is provided.
  • GC guanylate cyclase
  • the subject in need thereof is a vertebrate.
  • the subject is feline, canine, or equine.
  • the plasma concentration of the GC stimulator in the subject is higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18 pg/L, about 19 pg/L, or about 20 pg/L about 24 hours after administration of the oral suspension.
  • the plasma concentration of the GC stimulator in the subject is higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18 pg/L, about 19 pg/L, or about 20 pg/L about 48 hours after administration of the oral suspension.
  • the plasma concentration of the GC stimulator in the subject is higher than about 5 pg/L, about 6 pg/L, about 7 pg/L, about 8 pg/L, about 9 pg/L, about 10 pg/L, about 11 pg/L, about 12 pg/L, about 13 pg/L, about 14 pg/L, about 15 pg/L, about 16 pg/L, about 17 pg/L, about 18 pg/L, about 19 pg/L, or about 20 pg/L about 60 hours after administration of the oral suspension.
  • a dose of the GC stimulator administered to the subject is about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg about 1 mg/kg, about 1 .25 mg/kg, about 1.5 mg/kg, about 1 .75 mg/kg, or about 2 mg/kg.
  • a dose of the GC stimulator is administered to the subject four times per day, three times per day, twice per day, once per day, once per two days, once per week, once per month, once per two months, or once per three months.
  • the pharmaceutical formulation or oral suspension is voluntarily consumed by the subject.
  • one or more formulations of a GC stimulator described herein described herein further comprises a second GC stimulator and/or one or more additional therapeutic agent.
  • one or more methods of treatment described herein comprises administration of and/or one or more additional therapeutic agent.
  • one or more additional therapeutic agent is selected from those set forth in US Patent No. 10,052,312, which is incorporated by reference in its entirety.
  • one or more additional therapeutic agent is selected from those set forth in US Patent Application Publication No. US 2015/0274719.
  • the additional therapeutic agent is selected from (i) one or more organic nitrate and/or NO donor, optionally selected from sodium nitroprusside, nitroglycerin,
  • SUBSTITUTE SHEET (RULE 26) isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1 , or inhalational NO; (ii) one or more compound that inhibits the degradation of cyclic guanosine monophosphate (cGMP), optionally selected from inhibitors of phosphodiesterases (PDE) 1 , 2 and/or 5, optionally PDE-5 inhibitors, optionally sildenafil, vardenafil, or tadalafil; (iii) one or more antithrombotic agent, optionally selected from platelet aggregation inhibitors, optionally aspirin, clopidogrel, ticlopidine or dipyridamole; anticoagulants; thrombin inhibitors, optionally ximelagatran, dabigatran, melagatran, bivalirud in or Clexane; or prof ibrinolytic substances; (iv) one or more active substance for lowering blood pressure, optionally
  • Administration of one or more GC stimulators of the present disclosure with or in combination with one or more further therapeutic agents includes simultaneous (concurrent) and consecutive or sequential administration in any order.
  • concurrently is used herein to refer to administration of two or more therapeutic agents, where at least part of the administration overlaps in time or where the administration of one therapeutic agent falls within a short period of time relative to administration of the other therapeutic agent.
  • the two or more therapeutic agents are administered
  • SUBSTITUTE SHEET (RULE 26) with a time separation of no more than about a specified number of minutes.
  • subsequentially is used herein to refer to administration of two or more therapeutic agents where the administration of one or more agent(s) continues after discontinuing the administration of one or more other agent(s), or wherein administration of one or more agent(s) begins before the administration of one or more other agent(s).
  • administration of the two or more therapeutic agents are administered with a time separation of more than about a specified number of minutes.
  • in conjunction with refers to administration of one treatment modality in addition to another treatment modality.
  • in conjunction with refers to administration of one treatment modality before, during or after administration of the other treatment modality to the animal.
  • one or more of the formulations and/or methods described herein are used to treat and/or prevent diseases and/or conditions set forth in US Patent No. 10,052,312, which is incorporated by reference in its entirety. In some embodiments, one or more of the formulation(s) and/or method(s) described herein are used to treat and/or prevent diseases and/or conditions set forth in US Patent Application Publication No. US 2015/0274719. In some embodiments, one or more of the formulations and/or methods set forth herein is used to treat and/or prevent hypertension and/or one or more associated diseases.
  • the hypertension and/or associated diseases is one or more selected from hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular diseases, arrhythmias, disturbances of atrial and ventricular rhythm and conduction disturbances, for example atrioventricular blocks of degree l-lll (AVB l-lll), supraventricular tachyarrhythmia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsade-de-pointes tachycardia, atrial and ventricular extrasystoles, AV junction extrasystoles, sick-sinus syndrome, syncopes, AV-node reentry tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart diseases (pericarditis, endocarditis, valvulitis, aortiti
  • treatment is an approach for obtaining beneficial or desired clinical results.
  • Treatment covers any administration or application of a
  • SUBSTITUTE SHEET (RULE 26) therapeutic for disease in a mammal, including a companion animal.
  • beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total).
  • treatment is a reduction of pathological consequence of a proliferative disease.
  • the methods provided herein contemplate any one or more of these aspects of treatment. Inline with the above, the term treatment does not require one-hundred percent removal of all aspects of the disorder.
  • prevention or “prophylaxis” is an approach for obtaining beneficial or desired clinical results.
  • “Prevention” or “prophylaxis” as used herein covers any administration or application of a therapeutic for disease in a mammal, including a companion animal.
  • beneficial or desired clinical results include, but are not limited to, any one or more of: preventing or delaying occurrence of disease, preventing or delaying spread of disease, and/or preventing or delaying recurrence of disease.
  • prevention is a reduction, prevention, or delay of pathological consequence of a proliferative disease. The methods provided herein contemplate any one or more of these aspects of prevention. In-line with the above, the term prevention or prophylaxis does not require permanent prevention, but rather contemplates delas of any desirable period of time, such as by days, weeks, months, and/or years.
  • To “decrease”, “reduce”, or “inhibit” means to decrease, reduce, lower, or arrest an activity, function, or amount as compared to a reference. In some embodiments, by “decrease”, “reduce”, or “inhibit” is meant the ability to cause an overall decrease of 20% or greater. In some embodiments, by “decrease”, “reduce”, or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In some embodiments, by “decrease”, “reduce”, or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater.
  • the amount noted above is inhibited or decreased over a period of time, relative to a control dose (such as a placebo) over the same period of time.
  • a “reference” as used herein refers to any sample, standard, or level that is used for comparison purposes.
  • a reference may be obtained from a healthy or non-diseased sample.
  • a reference is obtained from a non-diseased or non-treated sample of a companion animal.
  • a reference is obtained from one or
  • SUBSTITUTE SHEET (RULE 26) more healthy animals of a particular species, which are not the animal being tested or treated.
  • a reference is an historical and/or population value obtained from a population of healthy animals and does not need to be measured in specific connection with the treatment.
  • blood pressure ranges considered normal for various species are generally known and, in some embodiments, are referred to in assessing, e.g., need for treatment, need for prevention, efficacy of treatment, and/or efficacy of prevention.
  • substantially reduced denotes a sufficiently high degree of reduction between a numeric value and a reference numeric value such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values.
  • the substantially reduced numeric values is reduced by greater than about any one of 10%, 15% 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the reference value.
  • one or more of the methods and/or formulations described herein decrease or substantially decrease a mean arterial blood pressure, a systolic blood pressure, and/or a diastolic blood pressure. In some embodiments, one or more of the methods described and/or formulations herein decrease a mean arterial blood pressure, a systolic blood pressure, and/or a diastolic blood pressure to about, to within about 1 %, to within about 2%, to within about 3%, to within about 4%, to within about 5%, to within about 10%, to within about 15%, or to within about 20% the blood pressure considered normal for the species treated.
  • one or more of the methods and/or formulations described herein prevent increase of a mean arterial blood pressure, a systolic blood pressure, and/or a diastolic blood pressure. In some embodiments, one or more of the methods and/or formulations described herein prevent increase of a mean arterial blood pressure, a systolic blood pressure, and/or a diastolic blood pressure to above about, to above about 1 %, to above about 2%, to above about 3%, to above about 4%, to above about 5%, to above about 10%, to above about 15%, or to above about 20% above the blood pressure considered normal for the species treated.
  • a canine may be considered to have a normal systolic blood pressure when it is in the range of about 110 to about 160 mm Hg or about 90 to about 140 mm Hg. In some embodiments, a canine may be considered to have a normal diastolic blood pressure when it is in the range of about 60 to about 90 mm Hg or about 50 to about 80 mm Hg. In some embodiments, a canine may be considered to have a normal
  • SUBSTITUTE SHEET mean arterial blood pressure when it is in the range of about 60 to about 100 mmHg.
  • a feline may be considered to have a normal systolic blood pressure when it is in the range of about 80 to about 140 mm Hg.
  • a feline may be considered to have a normal diastolic blood pressure when it is in the range of about 55 to about 75 mm Hg.
  • a feline may be considered to have a normal mean arterial blood pressure when it is in the range of about 60 to about 100 mmHg.
  • an equine may be considered to have a normal systolic blood pressure when it is in the range of about 105 to about 115 mm Hg. In some embodiments, an equine may be considered to have a normal diastolic blood pressure when it is in the range of about 65 to about 75 mm Hg. In some embodiments, an equine may be considered to have a normal mean arterial blood pressure when it is in the range of about 85 to about 95 mmHg.
  • ranges of values set forth herein are intended to operate as a scheme for referring to each separate value falling within the range individually, including but not limited to the endpoints of the ranges, and each separate
  • GC stimulator of the S enantiomer of Formula (I) and formulations comprising GC stimulator of the S enantiomer of Formula (I) were generated and evaluated using various procedures as set forth in the following examples.
  • GC stimulator of Formula (I) was purified using a high-performance liquid chromatography (HPLC) method.
  • HPLC high-performance liquid chromatography
  • the physicochemical properties of GC stimulator of Formula (I) and its stability and solubility data were determined by measuring a stirred sample of GC stimulator of Formula (I).
  • the stirred sample of GC stimulator of Formula (I) was prepared by stirring the GC stimulator of Formula (I) in toluene at 25°C for seven days.
  • the melting point of GC stimulator of Formula (I) was measured by a differential scanning calorimeter (DSC).
  • the melting point for both the unstirred and stirred samples of GC stimulator of Formula (I) is 174°C.
  • the unstirred sample shows a mass loss measured by thermal gravimetric analysis (TGA) of 0.3 %.
  • TGA thermal gravimetric analysis
  • the mass loss of the stirred sample is 0.2 %.
  • Sample of the GC stimulator of Formula (I) crystalline was stored at 90°C for one week. After storing the GC stimulator of Formula (I) crystalline at 90°C for one week, non-significant degradation was observed. Based on the results of the thermal stability test, it was believed that the GC stimulator of Formula (I) crystalline can be stored at room temperature in a tightly closed container for 6 months.
  • the hygroscopicity was determined by measuring a water sorption isotherm at 25°C.
  • the GC stimulator of Formula (I) crystalline is not hygroscopic.
  • Water uptake is 0.4% at 50% relative humidity (RH)/25°C and 0.7% at 95% RH/25°C.
  • UV/VIS radiation stability was determined by exposing the GC stimulator of Formula (I) under a light intensity of 200 Wh/m 2 for 24 hours.
  • Samples of solution (10’ 3 mol/l solution of Formula (I) in acetonitrile) and solid forms were placed in 10 mm and 0.5 mm quartz cells, respectively, and exposed to xenon light (Wh/m 2 ).
  • Control groups were tested under the same conditions and covered with aluminium foil.
  • sample of solution (0.05% of Formula (I) in acetonitrile) was exposed to daylight for 24 hours to simulate the laboratory handling.
  • GC stimulator of Formula (I) remained stable when being placed in an aqueous solvent for at least about 1 week under room temperature, or dissolving in an HCI solution of about 0.1 M for at least about 1 week under room temperature, or dissolving in a buffer with a pH value of about 10 for at least about 1 week under room temperature, or dissolving in a phosphate buffer with a pH value of about 7 for at least about 1 week under room temperature, with non-significant hydrolysis observed.
  • GC stimulator of Formula (I) crystalline was also tested for its per-oxidative stability.
  • Sample of GC stimulator of Formula (I) was placed in aqueous solvent with phosphate buffer adjusting the pH value to 7.
  • H2O2 was not added, the GC stimulator of Formula (I) remained stable under room temperature for 24 hours, with nonsignificant hydrolysis observed.
  • GC stimulator of Formula (I) was stored under per- oxidative conditions (0.05% Formula (I); 3 % H2O2 in phosphate buffer pH 7; addition of 50 % acetonitrile to improve solubility), a 99.5% degradation was observed after storing the sample under room temperature for 24 hours.
  • a Formulation (2) comprising a therapeutically effective amount of a GC stimulator of Formula (I) was prepared.
  • Formulation (2) was a suspension and was prepared by mixing the GC stimulator of Formula (I), dibasic sodium phosphate, citric acid, microcrystalline cellulose and carboxymethylcellulose sodium, ethylene oxide/propylene oxide copolymer, sodium hydroxide, hydrochloric acid, and water, in the amount listed in Table 7 below. Specifically, Batches were manufactured at 200 mL scale using a high
  • SUBSTITUTE SHEET (RULE 26) shear homogenizer (5 min at 8000 rpm) to activate the microcrystalline cellulose/carboxymethylcellulose sodium, followed by mixing all other ingredients with a stir bar/magnetic plate. Product was filled into 20 mL vials after completion of compounding. Three vials from beginning, middle, and end of filling process were analyzed for content uniformity.
  • Comparative Formulation (2) comprising a therapeutically effective amount of a GC stimulator of Formula (I) was also prepared.
  • Comparative Formulation (2) was a solution and was prepared by mixing the GC stimulator of Formula (I), dibasic sodium phosphate, citric acid, microcrystalline cellulose and carboxymethylcellulose sodium, ethylene oxide/propylene oxide copolymer, sodium hydroxide, hydrochloric acid, and water, in the amount listed in Table 8 below. Specifically, Batches were manufactured at 200 mL scale using a high shear homogenizer (5 min at 8000 rpm) to activate the microcrystalline cellulose/carboxymethylcellulose sodium, followed by mixing all other ingredients with a stir bar/magnetic plate. Product was filled into 20 mL vials after completion of compounding. Three vials from beginning, middle, and end of filling process were analyzed for content uniformity.
  • a Formulation (3) comprising a therapeutically effective amount of a GC stimulator of Formula (I) was prepared.
  • Formulation (3) was a suspension and was prepared by mixing the GC stimulator of Formula (I), dibasic sodium phosphate, citric acid, microcrystalline cellulose and carboxymethylcellulose sodium, ethylene oxide/propylene oxide copolymer, sodium hydroxide, hydrochloric acid, and water, in the amount listed in Table 10 below. The mixing process is similar to the process for preparing Formulation (2).
  • Comparative Formulation (3) comprising a therapeutically effective amount of a GC stimulator of Formula (I) was also prepared.
  • Comparative Formulation (3) was a suspension and included all the ingredients of Formulation (3).
  • methylparaben and propylpapaben were added as preservatives to Comparative Formulation (3).
  • the methyl and propyl paraben preservative system was selected due to prior art and efficacy at neutral pH.
  • the mixing process is similar to the process for preparing Formulation (2).
  • a Placebo Formulation (4) without preservatives and a Comparative Placebo Formulation (4) with preservatives were prepared.
  • the palatability of the formulations were assessed by observing the uptake of the formulations by cats, and compare that with the uptake of cat milk, with has a high palatability.
  • GC stimulator of Formula (I) was not added to either of the formulations to avoid negatively affecting the taste of the formulations.
  • the ingredients of the Placebo Formulation (4) and the Comparative Placebo Formulation (4) are listed in Table 12 below, and the results of the palatability study are listed in Table 13 below.
  • Placebo Formulation (4) with no preservatives added showed a palatability comparable to the positive control, whereas the Comparative Placebo Formulation (4) with preservatives added showed a significant decrease in palatability.
  • a revised Formulation (5) was prepared.
  • the ingredients of the Formulation (5) are listed in Table 14 below.
  • the objectives for the changes include: (a) increasing concentration of Formula (I) from 0.25% to 1 .0% to reduce dosing volume; (b) changing the citric acid monohydrate:dibasic sodium phosphate ratio to achieve target pH range (pH 6.5 -7.0) without sodium hydroxide/hydrochloric acid adjustment; (c) evaluating different grades and concentrations of microcrystalline cellulose/ carboxymethylcellulose sodium (Avicel CL 611 and Avicel RC 591 ) to improve physical stability of the formulation (reducing sedimentation rate and improving redispersibility); (d) substituting paraben preservatives with n-butyl alcohol due to the parabens’ low solubility (presenting challenges to assessing full dissolution in a suspension product or subsequent precipitation of the material on stability) and poor palatability; and (e) adding vanilla flavor to improve palatability.
  • FIG. 1 is a diagram showing the plasma concentration of GC stimulator of Formula (I) after administering Formulation (6) (Table 16) to fasted female European Shorthair Cats, with a dosage of 1 mg/kg of GC stimulator of Formula (I).
  • Table 16 Formulation (6)
  • Table 17 The parameters are listed in Table 17 below.
  • the open squares show the
  • SUBSTITUTE SHEET (RULE 26) concentrations for 1/ELC3, the open diamonds show the concentrations for 2/LJR4, and the open triangles show the concentrations for 3/LJY5.
  • FIGs. 2 and 3 are diagrams showing the plasma concentration of GC stimulator of Formula (I) after administering oily suspension and aqueous suspension in fed and fasted cats, with a dosage of 1 mg/kg of GC stimulator of Formula (I).
  • the PK parameters are listed in Table 18 below.
  • the ingredients of the oily suspension formulation (Formulation (7)) used in experiments of FIGs. 2 and 3 are listed in Table 19 of Example 8 below.
  • FIG. 2 shows the plasma concentration of Formula I after po administration of 1 mg/kg to fasted and fed female domestic shorthair cats.
  • the Y-axis in FIG. 2 is displayed in log scale.
  • the squares show the concentrations for fasted cats after administering the aqueous suspension
  • the blue circles show the concentrations for fasted cats after administering the oily suspension
  • the red circles show the concentrations for fed cats after administering the oily suspension.
  • FIG. 3 shows the plasma concentration of Formula I after po administration of 1 mg/kg to fasted and fed female domestic shorthair cats.
  • the Y-axis in FIG. 3 is displayed in linear scale.
  • the squares show the concentrations for fasted cats after administering the aqueous suspension
  • the blue circles show the concentrations for fasted cats after administering the oily suspension
  • the red circles show the concentrations for fed cats after administering the oily suspension.
  • the PK profile shown in FIGs. 1-3 demonstrate that the GC stimulator of Formula (I), after ingested, can stay in the plasma for a prolonged period.
  • the concentration of GC stimulator of Formula (I) can remain over 10 pg/L for 24 hours, or can remain over 10 pg/L for 48 hours, or can remain over 10 pg/L for 60 hours.
  • the cats were acclimatized to S Block prior to any dosing for at least 7 days. During the acclimatization period of the study, all cats had undergone a veterinary examination, and were weighed and systolic blood pressure (SBP) measured on at least three occasions.
  • SBP systolic blood pressure
  • the IVP vehicle placed on at least two occasions to train the cats to accept the liquid via syringe. The acceptance/rejection of the placebo also served as a tool to aid in the selection of the appropriate cats for this study. All cats had a baseline urine and blood sample collected for clinical pathology.
  • minor ailments e.g., minor skin lesions, tartar, gingivitis, mild ear or ocular discharge, etc.
  • SUBSTITUTE SHEET (RULE 26) investigational veterinary product/test item, hypertensive medication and/or antiinflammatory in the month prior to first treatment were excluded.
  • Davs 21 , 28, 35 and 42 pre-treatment and at 2 hours post-treatment for cohort A cats only.
  • Days 23, 30, 37 and 44 pre-treatment and at 2 hours post-treatment for cohort B cats only.
  • Blood samples for clinical pathology were collected pre-treatment and after the last treatment administration (Day 49) for each cat. Additional samples may be collected if required for investigation of an animal welfare concern.
  • Blood samples for determining the plasma pharmacokinetic (PK) profile of the IVP were collected from the treated cats (Groups 1 , 2 and 3) once pre-treatment and at approximately 2, 8 and 24 hours post-treatment on Days 5, 26 and 48, and on Day 51 (approximately 72 hours after the last treatment administration on Day 48).
  • a physical examination and blood pressure measurement will be performed. If post-treatment mean SBP measures ⁇ 90mmHg at any point in the study, the cat will be monitored closely, and blood pressure will be measured as required and immediately before the following treatment administration. If the mean SBP has increased to >90mmHg and in the absence of clinical signs, the cat may be treated. If the blood pressure has not increased and/or clinical signs persist the next treatment may be skipped and the following day the cat will return to the previous dose group (e.g., a cat in Group 2 will be dosed as Group 1 , and a cat in Group 3 will be dosed as Group 2).
  • the flow chart of Fig. 4 illustrates the blood pressure measurement plan.
  • All cats will be treated in a fasted state at approximately the same time each day from Day 0 to Day 48. Dosage will be calculated prior to first treatment according to treatment group allocation (Table 19) and individual body weights determined during acclimation (to an accuracy of 0.1 or 0.01 kg). The calculated dose of the IVP or CP will be rounded up to two decimal points, to the upper closest syringe gradation. IVP dose calculation will be calculated as follows:
  • the IVP was prepared and administered to the cats via syringe directly into their mouth.
  • the compound was dosed via capsules and if required, the formulation may also be offered on a plate for the cat to consume voluntarily. If a cat vomits after dosing, the cat will not be re-dosed until the next treatment day.
  • Feeding of cats influenced the investigated parameters in all study groups (Groups 1 -4 of Table 19). During feeding at approximately 4 hours post treatment with the test item and placebo, blood pressure values and heart rate of cats increased significantly in all study groups. Afterwards, blood pressure as well as heart rate decreased again to levels before feeding.
  • Formula (I) at the doses of 0.25 and 0.5mg/kg/day was very well tolerated in healthy normotensive conscious cats under the experimental conditions of the present study.
  • Formula (I) at 0.25 and 0.5 mg/kg/day mediated a statistically significant long lasting and dose-dependent decrease in mean, systolic and diastolic blood pressure.
  • Plasma protein binding assay was performed to evaluate the binding of Formula (I) to plasma proteins.
  • the assay was performed using an equilibrium dialysis method, and a fraction unbound (fu) value was measured.
  • the fu value is calculated by the formula below.
  • PC Concentration of Formula (I) in protein-containing compartment
  • PF Concentration of Formula (I) in protein-free compartment
  • Formula (I) stimulated the recombinant sGC concentration dependently from 0.01 to 100 pM with an effect of 1 .3 - to 177- fold.
  • the sGC stimulation induced by Formula (I) synergized with 2,2-Diethyl-1-nitroso-oxyhydrazine (DEA/NO) was nearly completely blocked by 1/-/-[1 ,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), and nearly absent in heme-free preparations.
  • DEA/NO 2,2-Diethyl-1-nitroso-oxyhydrazine
  • Formula (I) has a minimal effective concentration (MEC) at 70 nM and half maximal effective concentration (ECso) at 310 nM.
  • Formula (I) reduced coronary perfusion pressure concentration dependently from 1 nM to 10 pM with a maximal effect of about 40% at the highest concentration. Up to the highest concentration, Formula (I) had no effect on heart rate, left ventricular diastolic pressure, and contractility (dP/dt).
  • Platelet aggregation (plasma from human donors)
  • Formula (I) inhibited ADP (5-10 pM) induced aggregation
  • SUBSTITUTE SHEET (RULE 26) also inhibited collagen (3 pg/mL) induced aggregation in platelet rich plasma (ICso 15.6 pM).
  • Formula (I) caused an additional and long-lasting decrease in mean arterial blood pressure accompanied by reflex tachycardia.
  • the plasma clearance was 4.4 L/(h kg) in rats (moderate to high blood clearance), 1.6 L/(h kg) in dogs (moderate blood clearance) and 0.58 L/(h kg) in monkeys (low blood clearance).
  • the volume of distribution was high in all investigated species, with 16 L/kg in rats, 19 L/kg in dogs and 5.5 L/kg in monkeys.
  • the terminal elimination half-life of Formula (I) was 2.7 h in rats, 9.2 h in dogs and 7.1 h in monkeys.
  • SUBSTITUTE SHEET (RULE 26) absorption is limiting the oral bioavailability, which is in line with high extent of renal excretion of radioactivity after oral compared to iv administration as well as with in vitro data on moderate to high permeability in Caco-2 cells.
  • Formula (I) showed a preferential distribution into blood cells in rat, dog, and human (human: Cbiood/Cpiasma ratio 1 .34), whereas in monkey a concentration dependency of the partitioning was observed (0.90 at relevant concentrations in PK studies).
  • SUBSTITUTE SHEET (RULE 26) all species resulting from oxidative biotransformation: hydroxylation of the primary amine leading to M-1 , O-debenzylation yielding M-2 (most pronounced in rat) and hydroxylation of the difluorobenzyl moiety. Subsequent further oxidation/conjugation reactions or combinations thereof yielded several secondary metabolites.
  • Formula (I) revealed irreversible inhibition ofCYP3A4 with a partition ratio of about 300.
  • Formula (I) showed no induction of CYP1A2 and CYP3A4 up to the 6.9 pM in the test system.
  • Formula (I) is classified as a permeability glycoprotein (P-gp) substrate with efflux ratios between 10 and 1 at concentrations of 0.1 - 50 pM.
  • the efflux was saturable within the concentration range tested.
  • SUBSTITUTE SHEET (RULE 26) GLP Behavior (modified Irwin test), Loco-motor activity, Body temperature: rat/WU
  • Male rats were assessed for behavioral abnormalities and changes in body temperature at approximately 1 , 3, 6, and 24 h after treatment. At 6 and 24 h after administration, the animals were further tested for potential drug-induced changes in exploratory locomotor activity in an open field. At the low and mid dose level (0.3 and 1 mg/kg), a single oral administration of Formula (I) did not elicit symptoms of substantial behavioral abnormalities in male rats. Except for the occurrence of mushy feces in one of the vehicle-treated animals, the animals displayed normal behavior, both during handling and in the observation cages.
  • Formula (I) was associated with increased urination in 2 of 6 animals. Since this effect was seen infrequently and was fully reversible within 24 h, it was regarded not adverse. In the entire dose range tested, a single oral dose of Formula (I) did not interfere with locomotor activity in an open-field, body temperature regulation, and body weight of rats.
  • the No Observed Adverse Effect Level (NOAEL) for Formula (I) in rat is 3 mg/kg corresponding to plasma levels (C max ) of 49 pg/L.
  • the threshold of hemodynamic effects is 0.15 mg/kg at corresponding plasma levels (Cmax) of 2.6 pg/L. Due to the prominent reflex tachycardia at 1 .5 mg/kg, the NOAEL is regarded to be 0.5 mg/kg.
  • Formula (I) was tested in a Salmonella Microsome test for point mutations and in an in vitro and an in vivo micronucleus test for clastogenicity. All tests revealed negative results. Thus, Formula (I) is considered as non-genotoxic.
  • Formula (I) was tested in a GLP 2-week repeat-dose study in Wistar rats (10 animals/dose/sex), at daily oral doses of 0, 1 , 3 and 10 mg/kg bodyweight/day.
  • MTD maximum tolerated dose
  • Formula (I) revealed a toxicological profile in rats which is in line with those known from previous sGC stimulators.
  • reduced general condition mainly characterized by clinical findings and reduced body weight gain, was seen starting at 3 mg/kg.
  • effects on bone and gastrointestinal tract were seen.
  • the effects on RBC parameters and electrolytes as well as on creatinine and urea are seen as secondary to vasodilation and the changes of renal perfusion.
  • the NOAEL of the study is 1 mg/kg, based on body weight effects at 3 mg/kg and above.
  • SUBSTITUTE SHEET (RULE 26) clinical chemistry, urinalysis) and full post mortem examination including necropsy, organ weight analysis and microscopic examination.
  • the concentrations of Formula (I) were determined in plasma samples taken on day 1 and in week 2 at 0.5, 1 , 2, 4, 7, 24 and 48 h after administration respectively.
  • SUBSTITUTE SHEET (RULE 26) and 6 females were treated at doses of 0.5 - 1 .5 - 5 mg/kg as satellite animals for toxicokinetic evaluation.
  • Formula (I) shows light absorption in the range of 290 to 300 nm. However, in an in vitro 3T3 NRU phototoxicity test it was identified in as a non-phototoxic compound with a photo-irritation factor (PIF) of 1 .7.
  • PPF photo-irritation factor

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Abstract

L'invention concerne des formulations comprenant un stimulateur de guanylate cyclase (GC). Les formulations peuvent comprendre une suspension orale du stimulateur de GC. L'invention concerne également des méthodes de traitement de l'hypertension et/ou de maladies associées.
PCT/US2023/078897 2022-11-07 2023-11-07 Formulations de stimulateur de guanylate cyclase (gc) et leurs utilisations WO2024102699A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8198449B2 (en) * 2008-09-11 2012-06-12 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9126998B2 (en) * 2012-11-05 2015-09-08 Bayer Pharma AG Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US20150274719A1 (en) * 2012-11-05 2015-10-01 Bayer Pharma Aktiengesellschaft Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US20170101407A1 (en) * 2014-05-02 2017-04-13 Bayer Pharma Aktiengesellschaft 6-chlorine-substituted imidazo[1,2-a]pyridine carboxamides and the use thereof as soluble guanylate cyclase stimulators

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8198449B2 (en) * 2008-09-11 2012-06-12 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9126998B2 (en) * 2012-11-05 2015-09-08 Bayer Pharma AG Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US20150274719A1 (en) * 2012-11-05 2015-10-01 Bayer Pharma Aktiengesellschaft Amino-substituted imidazo[1,2-a]pyridinecarboxamides and their use
US20170101407A1 (en) * 2014-05-02 2017-04-13 Bayer Pharma Aktiengesellschaft 6-chlorine-substituted imidazo[1,2-a]pyridine carboxamides and the use thereof as soluble guanylate cyclase stimulators

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