US20100003193A1 - Unit dosage of apadenoson - Google Patents

Unit dosage of apadenoson Download PDF

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Publication number
US20100003193A1
US20100003193A1 US12/496,949 US49694909A US2010003193A1 US 20100003193 A1 US20100003193 A1 US 20100003193A1 US 49694909 A US49694909 A US 49694909A US 2010003193 A1 US2010003193 A1 US 2010003193A1
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Prior art keywords
unit dose
apadenoson
amount
saline
buffer
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US12/496,949
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Robert Hendel
William B. Stilley
Shannon P. Williams
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UVA Licensing and Ventures Group
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University of Virginia Patent Foundation
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Priority to US12/496,949 priority Critical patent/US20100003193A1/en
Assigned to VIRGINIA, UNIVERSITY OF reassignment VIRGINIA, UNIVERSITY OF ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STILLEY, WILLIAM B., WILLIAMS, SHANNON P., HENDEL, ROBERT
Publication of US20100003193A1 publication Critical patent/US20100003193A1/en
Assigned to UNIVERSITY OF VIRGINIA PATENT FOUNDATION reassignment UNIVERSITY OF VIRGINIA PATENT FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF VIRGINIA
Assigned to UNIVERSITY OF VIRGINIA PATENT FOUNDATION reassignment UNIVERSITY OF VIRGINIA PATENT FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF VIRGINIA
Priority to US13/544,364 priority patent/US20130017153A1/en
Priority to US14/103,130 priority patent/US9415058B2/en
Priority to US15/181,235 priority patent/US9662406B2/en
Priority to US15/600,303 priority patent/US20170252463A1/en
Priority to US16/045,359 priority patent/US20190022253A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a unit dosage of Apadenoson, a pharmacological stress agent, and use of the same as a pharmacologic agent for myocardial perfusion imaging.
  • Apadenoson shown below, was first described as a pharmacologic stress agent
  • Dr. Hendel et al reported to the American Heart Association on the preliminary results of 127 patient SPECT Tc 99m sestamibi imaging studying comparing adenosine with Apadenoson using either 1 ⁇ g/kg or 2 ⁇ g/kg intravenous boluses of Apadenoson. The report concluded that Apadenoson was safe and well-tolerated and worthy of Phase III evaluation. In 2006, Dr.
  • Kern et al reported to the American Heart Association the results of a Phase II study of Apadenoson, one goal of which was to determine an appropriate dose for Phase III clinical trials.
  • Intravenous bolus dosages of 0.5, 1.0, 2.0, and 2.5 ⁇ g/kg were studied.
  • the average peak velocity for coronary blood flow was shown to increase with a corresponding increase in dosage from 0.5 to 2 ⁇ g/kg (see FIG. 1 ).
  • Apadenoson would need to be administered on a weight basis, not a unit dose basis.
  • the present invention provides a novel unit dose of Apadenoson suitable for parenteral administration.
  • the present invention also provides a novel method of diagnosing myocardial dysfunction using a unit dose of Apadenoson as a pharmacologic stress agent.
  • FIG. 1 shows the average peak flow wire velocity of one patient from a Phase II clinical trial study.
  • adenosine was administered by intracoronary injection, and coronary blood flow velocity was monitored with a flow wire.
  • the three injections of adenosine increased blood flow velocity consistent with the well characterized pharmacology of adenosine.
  • increasing bolus doses of Apadenoson at doses shown to be safe, achieved peak flow equivalent to adenosine.
  • FIG. 2 shows the average peak flow wire velocity of 33 patients from the study described in FIG. 1 .
  • CBFV coronary blood flow velocity
  • the present invention provides a novel unit dose of Apadenoson, comprising: (a) Apadenoson and (b) a pharmaceutically acceptable carrier, wherein the unit dose is suitable for parenteral administration.
  • the unit dose is suitable for intravenous administration.
  • the amount of Apadenoson present in the unit dose is selected from 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158,
  • the amount of Apadenoson present in the unit dose is in the range selected from 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, to 125 ⁇ g. Additional examples of the weight of Apadenoson present include (a) 115, 120, and 125 ⁇ g and (b) 120 ⁇ g.
  • the pharmaceutical carrier comprises: a cyclodextrin.
  • cyclodextrins include ⁇ -CD or derivatives thereof (e.g., ⁇ -hydroxypropyl-CD (HP- ⁇ -CD)), ⁇ -CD or derivatives thereof (e.g., ⁇ -hydroxypropyl-CD (HP- ⁇ -CD), methylated ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, and sulfobutylether ⁇ -CD), and ⁇ -CD or derivatives thereof (e.g., ⁇ -hydroxypropyl-CD (HP- ⁇ -CD)).
  • concentration of CD examples include being within the range selected from (a) about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10% w/v; (b) about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, to 4% w/v; (c) about 1% w/v; and, (d) about 2% w/v of the final formulation.
  • CD e.g., hydroxypropyl- ⁇ -cyclodextrin
  • the pharmaceutical carrier comprises: buffered saline.
  • a useful buffer is a citrate buffer (e.g., sodium citrate).
  • Citric acid can be useful to adjust the pH of the unit dose.
  • the pharmaceutical carrier comprises: buffered saline, comprising: saline, sodium citrate, and citric acid.
  • buffered saline comprising: saline, sodium citrate, and citric acid.
  • citric acid may not be present in the final unit dose due to ionization.
  • the pH of the unit dose is selected from 4.6, 4.7, 4.8, 4.9, to 5.0.
  • Another example of the pH of the unit does is 4.8.
  • the volume of the unit dose is selected from 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 mL.
  • Another example of the volume is from 2, 3, 4, to 5 mL.
  • the unit dose comprises:
  • the unit dose comprises:
  • the unit dose comprises:
  • the unit dose comprises:
  • the unit dose of the present invention can be filled into any useful container for storage, transportation, and usage.
  • An example of a useful container is a syringe body.
  • the present invention provides a novel method of diagnosing myocardial perfusion abnormalities in a mammal, comprising:
  • the patient weighs at least 40 kg.
  • the administration is intravenous administration.
  • the technique is an imaging technique selected from: planar or single photon emission computed tomography (SPECT), gamma camera scintigraphy, positron emission tomography (PET), nuclear magnetic resonance (NMR) imaging, magnetic resonance imaging (MRI) imaging, perfusion contrast echocardiography, digital subtraction angiography (DSA), and ultrafast X-ray computed tomography (CINE CT).
  • SPECT planar or single photon emission computed tomography
  • PET gamma camera scintigraphy
  • PET positron emission tomography
  • NMR nuclear magnetic resonance
  • MRI magnetic resonance imaging
  • DSA digital subtraction angiography
  • CINE CT ultrafast X-ray computed tomography
  • the present invention provides a prefilled syringe, comprising: a syringe and a unit dose of Apadenoson, comprising: (a) Apadenoson and (b) a pharmaceutically acceptable carrier, wherein the unit dose is suitable for parenteral administration.
  • the syringe can be any known syringe useful for parenteral administration.
  • the syringe can comprise: a body and a plunger movably disposed within the body.
  • the body can be cylindrical with a first open end to receive the plunger and a second end opposite the first, with the second end modified with an opening sufficient for the unit dose to pass through.
  • the syringe can further comprise: a needle (e.g., an injection needle).
  • the needle can be detachably connected to or permanently fixed to the body.
  • a needle guard can also be present
  • the present invention provides a novel unit dose of Apadenoson for use in medical therapy.
  • the present invention provides a novel use of a unit dose of Apadenoson for the manufacture of a medicament for use in diagnosing myocardial perfusion abnormalities in a mammal.
  • the Apadenoson unit dose of the present invention can be administered as a pharmacological stress agent and used in conjunction with any one of several noninvasive diagnostic procedures to measure aspects of myocardial, coronary, and/or ventricular perfusion.
  • Aspects that can be measured include coronary artery stenoses, myocardial dysfunction (e.g., myocardial ischemia, coronary artery disease, ventricular dysfunction, and differences in blood flow through disease-free coronary vessels and/or stenotic coronary vessels), myocardial contractile dysfunction, the presence of regional wall motion abnormalities, the functional significance of stenotic coronary vessels, coronary artery disease, ischemic ventricular dysfunction, and vasodilatory capacity (reserve capacity) of coronary arteries in humans.
  • myocardial dysfunction e.g., myocardial ischemia, coronary artery disease, ventricular dysfunction, and differences in blood flow through disease-free coronary vessels and/or stenotic coronary vessels
  • myocardial contractile dysfunction e.
  • Radiopharmaceuticals are typically used in diagnostic method methods.
  • the radiopharmaceutical agent may comprise, for example, a radionuclide selected from the group consisting of thallium-201, technetium-99 m , nitrogen-13, rubidium-82, iodine-123 and oxygen-15.
  • Unit dose means the amount of a medication administered to a patient in a single dose.
  • a unit dose is typically independent of the weight of the patient or may be associated with a specified weight range (e.g., ⁇ 40kg).
  • Mammal and patient covers warm blooded mammals that are typically under medical care (e.g., humans and domesticated animals). Examples of mammals include (a) feline, canine, equine, and bovine and (b) human.
  • Parenteral includes intravenous, intramuscular, and subcutaneous routes.
  • Sterile injectable solutions are typically prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization (or some other form of sterilization).
  • filter sterilization or some other form of sterilization.
  • the methods of preparation include vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

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Abstract

The present invention provides a unit dosage of Apadenoson, a pharmacological stress agent, and use of the same as a pharmacologic agent for myocardial perfusion imaging.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • The present application claims the priority benefits of U.S. Provisional Applications No. 61/078,169, filed 3 Jul. 2008 and No. 61/155,937, filed 27 Feb. 2009, which are expressly incorporated fully herein by reference.
    • FIELD OF THE INVENTION
  • The present invention relates to a unit dosage of Apadenoson, a pharmacological stress agent, and use of the same as a pharmacologic agent for myocardial perfusion imaging.
    • BACKGROUND OF THE INVENTION
  • Apadenoson, shown below, was first described as a pharmacologic stress agent
  • Figure US20100003193A1-20100107-C00001
  • that can be used in clinical perfusion imaging techniques (e.g., for diagnosing and assessing the extent of coronary artery disease) in U.S. Pat. No. 6,322,771. This agent has since been taken into Phase I and II clinical trials. In 2005, Dr. Hendel et al reported to the American Heart Association on the preliminary results of 127 patient SPECT Tc99m sestamibi imaging studying comparing adenosine with Apadenoson using either 1 μg/kg or 2 μg/kg intravenous boluses of Apadenoson. The report concluded that Apadenoson was safe and well-tolerated and worthy of Phase III evaluation. In 2006, Dr. Kern et al reported to the American Heart Association the results of a Phase II study of Apadenoson, one goal of which was to determine an appropriate dose for Phase III clinical trials. Intravenous bolus dosages of 0.5, 1.0, 2.0, and 2.5 μg/kg were studied. For a patients, the average peak velocity for coronary blood flow was shown to increase with a corresponding increase in dosage from 0.5 to 2 μg/kg (see FIG. 1). In light of this data, it was believed that Apadenoson would need to be administered on a weight basis, not a unit dose basis.
  • There are inherent limitations and opportunities for operator error when parenterally administering a pharmaceutical agent on a weight basis. This type of dosing requires calculating the amount of agent to administer based on a patient's weight, administering the calculated amount from a larger dose, and disposing of any left over agent. Thus, it is desirable and beneficial for a pharmaceutical agent to be provided in a unit dose.
    • SUMMARY OF THE INVENTION
  • The present invention provides a novel unit dose of Apadenoson suitable for parenteral administration.
  • The present invention also provides a novel method of diagnosing myocardial dysfunction using a unit dose of Apadenoson as a pharmacologic stress agent.
  • These and other aspects of the present invention have been accomplished in view of the discovery that no dose response curve is seen when 1 μg/kg or 2 μg/kg of Apadenoson is administered.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows the average peak flow wire velocity of one patient from a Phase II clinical trial study. In this Phase II study in 100 patients, conducted by Dr. Morton Kern, an independent investigator at UC Irvine, adenosine was administered by intracoronary injection, and coronary blood flow velocity was monitored with a flow wire. On the left, the three injections of adenosine increased blood flow velocity consistent with the well characterized pharmacology of adenosine. On the right, increasing bolus doses of Apadenoson, at doses shown to be safe, achieved peak flow equivalent to adenosine.
  • FIG. 2 shows the average peak flow wire velocity of 33 patients from the study described in FIG. 1.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The previously reported increase in coronary blood flow velocity (CBFV) corresponding to an increase in dose of Apadenoson from 0.5 to 2 μg/kg was based on the increase in CBFV in a limited number of patients (see FIG. 1). However, it has now been found that if one considers the entire sample of patients, as shown in FIG. 2, then at dose >1μg/kg and in particular between 1 and 2.5 μg/kg no dose response is seen. In light of this, Applicant has surprisingly discovered that instead of the weight-based dosing predicted by the results reported in FIG. 1, Apadenson can actually be administered via a unit dose.
  • Thus, in an embodiment, the present invention provides a novel unit dose of Apadenoson, comprising: (a) Apadenoson and (b) a pharmaceutically acceptable carrier, wherein the unit dose is suitable for parenteral administration.
  • In another embodiment, the unit dose is suitable for intravenous administration.
  • In another embodiment, the amount of Apadenoson present in the unit dose is selected from 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, and 175 μg. Additional examples of the weight of Apadenoson present include (a) 100, 110, 120, 130, 140, and 150 μg; (b) 100 μg; and (c) 150 μg.
  • In another embodiment, the amount of Apadenoson present in the unit dose is in the range selected from 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, to 125μg. Additional examples of the weight of Apadenoson present include (a) 115, 120, and 125 μg and (b) 120 μg.
  • In another embodiment, the pharmaceutical carrier, comprises: a cyclodextrin. Examples of cyclodextrins include α-CD or derivatives thereof (e.g., α-hydroxypropyl-CD (HP-α-CD)), β-CD or derivatives thereof (e.g., β-hydroxypropyl-CD (HP-β-CD), methylated β-cyclodextrin, hydroxyethyl-β-cyclodextrin, and sulfobutylether β-CD), and γ-CD or derivatives thereof (e.g., γ-hydroxypropyl-CD (HP-γ-CD)).
  • Examples of the concentration of CD (e.g., hydroxypropyl-β-cyclodextrin) include being within the range selected from (a) about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10% w/v; (b) about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, to 4% w/v; (c) about 1% w/v; and, (d) about 2% w/v of the final formulation.
  • In another embodiment, the pharmaceutical carrier, comprises: buffered saline. A useful buffer is a citrate buffer (e.g., sodium citrate). Citric acid can be useful to adjust the pH of the unit dose. As an example, the pharmaceutical carrier, comprises: buffered saline, comprising: saline, sodium citrate, and citric acid. One would recognize that citric acid may not be present in the final unit dose due to ionization.
  • In another embodiment, the pH of the unit dose is selected from 4.6, 4.7, 4.8, 4.9, to 5.0. Another example of the pH of the unit does is 4.8.
  • In another embodiment, the volume of the unit dose is selected from 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 mL. Another example of the volume is from 2, 3, 4, to 5 mL.
  • In another embodiment, the unit dose, comprises:
      • (a) 100 μg Apadenoson;
      • (b) a pharmaceutically acceptable carrier, comprising:
        • (bi) 2% w/v HP-β-CD;
        • (bii) sodium citrate buffer in an amount to buffer the unit dose to pH 4.8; and,
        • (biii) saline in an amount to form a 1-5 mL unit dose.
  • In another embodiment, the unit dose, comprises:
      • (a) 100 μg Apadenoson;
      • (b) a pharmaceutically acceptable carrier, comprising:
        • (bi) 1% w/v HP-β-CD;
        • (bii) sodium citrate buffer in an amount to buffer the unit dose to pH 4.8; and,
        • (biii) saline in an amount to form a 1-5 mL unit dose.
  • In another embodiment, the unit dose, comprises:
      • (a) 150 μg Apadenoson;
      • (b) a pharmaceutically acceptable carrier, comprising:
        • (bi) 2% w/v HP-β-CD;
        • (bii) sodium citrate buffer in an amount to buffer the unit dose to pH 4.8; and,
        • (biii) saline in an amount to form a 1-5 mL unit dose.
  • In another embodiment, the unit dose, comprises:
      • (a) 150 μg Apadenoson;
      • (b) a pharmaceutically acceptable carrier, comprising:
        • (bi) 2% w/v HP-β-CD;
        • (bii) sodium citrate buffer in an amount to buffer the unit dose to pH 4.8; and,
        • (biii) saline in an amount to form a 1-5 mL unit dose.
  • The unit dose of the present invention can be filled into any useful container for storage, transportation, and usage. An example of a useful container is a syringe body.
  • In another embodiment, the present invention provides a novel method of diagnosing myocardial perfusion abnormalities in a mammal, comprising:
      • (a) parenterally administering to the mammal a unit dose of Apadenoson; and
      • (b) performing a technique on the mammal to detect the presence of coronary artery stenoses, assess the severity of coronary artery stenoses, or a combination thereof.
  • In another embodiment, the patient weighs at least 40 kg.
  • In another embodiment, the administration is intravenous administration.
  • In another embodiment, the technique is an imaging technique selected from: planar or single photon emission computed tomography (SPECT), gamma camera scintigraphy, positron emission tomography (PET), nuclear magnetic resonance (NMR) imaging, magnetic resonance imaging (MRI) imaging, perfusion contrast echocardiography, digital subtraction angiography (DSA), and ultrafast X-ray computed tomography (CINE CT).
  • In another embodiment, the present invention provides a prefilled syringe, comprising: a syringe and a unit dose of Apadenoson, comprising: (a) Apadenoson and (b) a pharmaceutically acceptable carrier, wherein the unit dose is suitable for parenteral administration. The syringe can be any known syringe useful for parenteral administration. For example, the syringe can comprise: a body and a plunger movably disposed within the body. The body can be cylindrical with a first open end to receive the plunger and a second end opposite the first, with the second end modified with an opening sufficient for the unit dose to pass through. The syringe can further comprise: a needle (e.g., an injection needle). The needle can be detachably connected to or permanently fixed to the body. A needle guard can also be present
  • In another embodiment, the present invention provides a novel unit dose of Apadenoson for use in medical therapy.
  • In another embodiment, the present invention provides a novel use of a unit dose of Apadenoson for the manufacture of a medicament for use in diagnosing myocardial perfusion abnormalities in a mammal.
  • The Apadenoson unit dose of the present invention can be administered as a pharmacological stress agent and used in conjunction with any one of several noninvasive diagnostic procedures to measure aspects of myocardial, coronary, and/or ventricular perfusion. Aspects that can be measured include coronary artery stenoses, myocardial dysfunction (e.g., myocardial ischemia, coronary artery disease, ventricular dysfunction, and differences in blood flow through disease-free coronary vessels and/or stenotic coronary vessels), myocardial contractile dysfunction, the presence of regional wall motion abnormalities, the functional significance of stenotic coronary vessels, coronary artery disease, ischemic ventricular dysfunction, and vasodilatory capacity (reserve capacity) of coronary arteries in humans. Radiopharmaceuticals are typically used in diagnostic method methods. The radiopharmaceutical agent may comprise, for example, a radionuclide selected from the group consisting of thallium-201, technetium-99m, nitrogen-13, rubidium-82, iodine-123 and oxygen-15.
  • Any embodiment or feature of the present invention whether characterized as preferred or not characterized as preferred may be combined with any other aspect or feature of the invention, whether such other feature is characterized as preferred or not characterized as preferred.
  • Definitions
  • The examples provided in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited groups.
  • Unit dose means the amount of a medication administered to a patient in a single dose. A unit dose is typically independent of the weight of the patient or may be associated with a specified weight range (e.g., ≧40kg).
  • The indefinite articles “a” and “an” mean “at least one” or “one or more” when used in this application, including the claims, unless specifically indicated otherwise.
  • Mammal and patient covers warm blooded mammals that are typically under medical care (e.g., humans and domesticated animals). Examples of mammals include (a) feline, canine, equine, and bovine and (b) human.
  • Parenteral includes intravenous, intramuscular, and subcutaneous routes.
  • Dosage and formulation
  • Sterile injectable solutions are typically prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization (or some other form of sterilization). In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation include vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • All patents, patent applications, books and literature cited in the specification are hereby incorporated by reference in their entirety. In the case of any inconsistencies, the present disclosure, including any definitions therein will prevail.
  • Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein.

Claims (21)

1. A unit dose of Apadenoson, comprising: (a) Apadenoson and (b) a pharmaceutically acceptable carrier, wherein the unit dose is suitable for parenteral administration.
2. The unit dose of claim 1, wherein the amount of Apadenoson present is selected from 76-175 μg.
3. The unit dose of claim 2, wherein the amount of Apadenoson present is selected from 100-150 μg.
4. The unit dose of claim 3, wherein the amount of Apadenoson present is 100 μg.
5. The unit dose of claim 3, wherein the amount of Apadenoson present is 150 μg.
6. The unit dose of claim 1, wherein the pharmaceutical carrier, comprises: a cyclodextrin (CD).
7. The unit dose of claim 6, wherein the cyclodextrin is β-hydroxypropyl-CD.
8. The unit dose of claim 6, wherein the concentration of CD is selected from 0.1-10% w/v of the final formulation.
9. The unit dose of claim 8, wherein the concentration of CD is 1% w/v.
10. The unit dose of claim 8, wherein the concentration of CD is 2% w/v.
11. The unit does of claim 1, wherein the pharmaceutical carrier, comprises: buffered saline.
12. The unit dose of claim 11, wherein the pharmaceutical carrier, comprises: buffered saline, comprising: saline and sodium citrate.
13. The unit dose of claim 1, wherein the pH of the unit dose is selected from 4.6-5.0.
14. The unit dose of claim 13, wherein the pH is 4.8.
15. The unit dose of claim 1, wherein the volume of the unit dose is selected from 1-5 mL.
16. The unit dose of claim 1, comprising:
(a) 100 μg Apadenoson;
(b) a pharmaceutically acceptable carrier, comprising:
(bi) 2% w/v HP-β-CD;
(bii) sodium citrate buffer in an amount to buffer the unit dose to pH 4.8; and,
(biii) saline in an amount to form a 1-5 mL unit dose.
17. The unit dose of claim 1, comprising:
(a) 100 μg Apadenoson;
(b) a pharmaceutically acceptable carrier, comprising:
(bi) 1% w/v HP-β-CD;
(bii) sodium citrate buffer in an amount to buffer the unit dose to pH 4.8; and,
(biii) saline in an amount to form a 1-5 mL unit dose.
18. The unit dose of claim 1, comprising:
(a) 150 μg Apadenoson;
(b) a pharmaceutically acceptable carrier, comprising:
(bi) 2% w/v HP-β-CD;
(bii) sodium citrate buffer in an amount to buffer the unit dose to pH 4.8; and,
(biii) saline in an amount to form a 1-5 mL unit dose.
19. The unit dose of claim 1, comprising:
(a) 150 μg Apadenoson;
(b) a pharmaceutically acceptable carrier, comprising:
(bi) 2% w/v HP-β-CD;
(bii) sodium citrate buffer in an amount to buffer the unit dose to pH 4.8; and,
(biii) saline in an amount to form a 1-5 mL unit dose.
20. A method of diagnosing myocardial perfusion abnormalities in a mammal, comprising:
(a) parenterally administering to the mammal a unit dose of Apadenoson; and
(b) performing a technique on the mammal to detect the presence of coronary artery stenoses, assess the severity of coronary artery stenoses, or a combination thereof.
21. The method of claim 20, wherein the patient weighs at least 40 kg.
US12/496,949 2008-07-03 2009-07-02 Unit dosage of apadenoson Abandoned US20100003193A1 (en)

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US13/544,364 US20130017153A1 (en) 2008-07-03 2012-07-09 Unit dosage of apadenoson
US14/103,130 US9415058B2 (en) 2008-07-03 2013-12-11 Unit dosage of Apadenoson
US15/181,235 US9662406B2 (en) 2008-07-03 2016-06-13 Unit dosage of apadenoson
US15/600,303 US20170252463A1 (en) 2008-07-03 2017-05-19 Unit dosage of apadenoson
US16/045,359 US20190022253A1 (en) 2008-07-03 2018-07-25 Unit dosage of apadenoson

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