# Patent

## Title
Unit dosage of apadenoson

## 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.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of U.S. patent application Ser. No. 14/103,130, filed on Dec. 11, 2013, now U.S. Patent No. 9,415,058, issued 16 Aug. 2016, which is a divisional of U.S. patent application Ser. No. 13/544,364, filed on Jul. 9, 2012, now abandoned, which is a continuation of U.S. patent application Ser. No. 12/496,949, filed on Jul. 2, 2009, now abandoned, which claims the priority benefits of U.S. Provisional Applications No. 61/078,169, filed Jul. 3, 2008 and No. 61/155,937, filed Feb. 27 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




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 ≧1 μg/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 125 μg. 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

1. A method of chemically inducing stress and diagnosing myocardial perfusion abnormalities in a mammal, comprising:
(a) selecting a dose of Apadenoson between about 76-175 μg on a basis that is independent of the weight of the mammal to whom the dose will be administered;
(b) administering to said mammal, via bolus, the dose of Apadenoson as a unit dose comprising Apadenson and a pharmaceutically acceptable carrier; and
(c) performing a technique to detect the presence of coronary artery stenoses in the mammal, to assess the severity of coronary artery stenoses in the mammal, or a combination thereof, so as to diagnose myocardial perfusion abnormalities in said mammal.

2. The method of claim 1, wherein the unit dose further contains an effective amount of β-hydroxypropyl-cyclodextrin (HP-β-CD).

3. The method of claim 2, wherein the amount of HP-β-CD is about 0.1-10% w/v of the final formulation.

4. The method of claim 2, wherein the amount of HP-β-CD is 1% w/v.

5. The method of claim 1, wherein the dose of Apadenoson is 76 μg.

6. The method of claim 1, wherein the dose of Apadenoson is 110 μg.

7. The method of claim 1, wherein the dose of Apadenoson is 115 μg.

8. The method of claim 1, wherein the dose of Apadenoson is 120 μg.

9. The method of claim 1, wherein the dose of Apadenoson is 125 μg.

10. The method of claim 1, wherein the dose of Apadenoson is 130 μg.

11. The method of claim 1, wherein the dose of Apadenoson is 140 μg.

12. The method of claim 1, wherein the unit dose is 1 mL in volume.

13. The method of claim 1, wherein the unit dose is 2 mL in volume.

14. The method of claim 1, wherein the unit dose is 3 mL in volume.

15. The method of claim 1, wherein the unit dose is 4 mL in volume.

16. The method of claim 1, wherein the unit dose is 5 mL in volume.

17. The method of claim 1, wherein the dose of Apadenoson is selected on the basis of a single weight of Apadenoson being effective in previously tested mammals having a range of different weights.

18. The method of claim 1, wherein the unit dose further contains sodium citrate buffer.

19. The method of claim 18, wherein sodium citrate buffer is present in an amount to buffer the unit dose to pH selected from 4.6-5.0.