U.S. patent application number 12/014949 was filed with the patent office on 2008-09-11 for adenosine derivative formulations for medical imaging.
Invention is credited to James E. Anderson, James F. Castner, Hsun-Wen Hsu, Ajit B. Thakur, Dianne D. Zdankiewicz.
Application Number | 20080219927 12/014949 |
Document ID | / |
Family ID | 39636305 |
Filed Date | 2008-09-11 |
United States Patent
Application |
20080219927 |
Kind Code |
A1 |
Thakur; Ajit B. ; et
al. |
September 11, 2008 |
ADENOSINE DERIVATIVE FORMULATIONS FOR MEDICAL IMAGING
Abstract
A stable composition useful for myocardial perfusion imaging
contains one or more 2-alkynyladenosine derivatives; and a solvent
which is made up of water and
hydroxypropyl-.beta.-cyclodextrin.
Inventors: |
Thakur; Ajit B.; (East
Brunswick, NJ) ; Zdankiewicz; Dianne D.;
(Londonberry, NH) ; Hsu; Hsun-Wen; (Woburn,
MA) ; Castner; James F.; (Groton, MA) ;
Anderson; James E.; (Hudson, MA) |
Correspondence
Address: |
WILLIAMS MULLEN
222 CENTRAL PARK AVENUE, SUITE 1700
VIRGINIA BEACH
VA
23462
US
|
Family ID: |
39636305 |
Appl. No.: |
12/014949 |
Filed: |
January 16, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60885489 |
Jan 18, 2007 |
|
|
|
Current U.S.
Class: |
424/9.1 ;
514/46 |
Current CPC
Class: |
A61K 47/6951 20170801;
B82Y 5/00 20130101; A61K 49/0002 20130101; A61P 9/08 20180101 |
Class at
Publication: |
424/9.1 ;
514/46 |
International
Class: |
A61K 49/00 20060101
A61K049/00; A61K 31/7076 20060101 A61K031/7076 |
Claims
1. A stable composition useful for myocardial perfusion imaging,
comprising: (a) an adenosine derivative, which is methyl
trans-4-[3-[6-amino-9-(N-ethyl-.beta.-D-ribofuranosyluronamide)-9H-purin--
2-yl]prop-2-ynyl]cyclohexane carboxylate or a pharmaceutically
acceptable salt thereof; and, (b) a solvent consisting essentially
of water and hydroxypropyl-.beta.-cyclodextrin.
2. The composition of claim 1, further comprising a buffer.
3. The composition of claim 2, wherein the buffer comprises: sodium
citrate and citric acid.
4. The composition of claim 1, wherein the concentration of
hydroxypropyl-.beta.-cyclodextrin is about 0.1-10% w/v.
5. The composition of claim 4, wherein the concentration of
hydroxypropyl-.beta.-cyclodextrin is about 0.5-2% w/v.
6. The composition of claim 1, wherein the molar ratio of the
adenosine derivative to hydroxypropyl-.beta.-cyclodextrin is about
1:30 to 1:150.
7. The composition of claim 1, wherein
hydroxyethyl-.beta.-cyclodextrin is absent from the
composition.
8. The composition of claim 1, wherein any other
.beta.-cyclodextrin is absent from the composition.
9. The composition of claim 1, wherein any other solvent is absent
from the composition.
10. The composition of claim 1, wherein the composition is storage
stable for at least about 3 months.
11. A method of inducing cardiovascular stress, which comprises
administering to a patient a pharmacologic vasodilation
formulation, comprising: (a) an adenosine derivative, which is
methyl
trans-4-[3-[6-amino-9-(N-ethyl-.beta.-D-ribofuranosyluronamide)-9H-purin--
2-yl]prop-2-ynyl]cyclohexane carboxylate or a pharmaceutically
acceptable salt thereof, (b) a solvent consisting essentially of
water and hydroxypropyl-.beta.-cyclodextrin; and, (c) buffer.
12. The method of claim 11, wherein the composition is administered
intravenously.
13. The method of claim 11, wherein the adenosine derivative is
administered at a dose not exceeding about 5 mcg/kg of body
weight.
14. The method of claim 13, wherein the adenosine derivative is
administered at a dose not exceeding about 2 mcg/kg of body
weight.
15. The method of claim 11, wherein the adenosine derivative is
administered at a dose within the range of about 0.5-5 mcg/kg.
16. The method of claim 11, wherein the adenosine derivative is
administered via an intracoronary route to the human in a dose of
about 0.05-0.5 mcg thereof sufficient to provide coronary artery
dilation.
17. A cardiovascular stress testing kit, comprising: (a) an
adenosine derivative, which is methyl
trans-4-[3-[6-amino-9-(N-ethyl-.beta.-D-ribofuranosyluronamide)-9H-purin--
2-yl]prop-2-ynyl]cyclohexane carboxylate or a pharmaceutically
acceptable salt thereof; and, (b) a solvent consisting essentially
of water and hydroxypropyl-.beta.-cyclodextrin.
18. The kit of claim 17, wherein hydroxyethyl-.beta.-cyclodextrin
is absent from the solvent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the priority benefits of U.S.
Provisional Application No. 60/885,489, filed 18 Jan. 2007, which
is expressly incorporated fully herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to novel formulations of
adenosine derivatives which are storage stable and useful for
medical imaging, in particular myocardial perfusion imaging.
BACKGROUND OF THE INVENTION
[0003] Adequate coronary vasodilation is essential to myocardial
perfusion imaging. Coronary vasodilation increases coronary blood
flow. This increase creates differences in the distribution of the
imaging agent great enough to identify regions supplied by stenosed
coronary vessels and to distinguish problem areas from healthy
tissue.
[0004] Exercise stress testing often is employed for dilating
coronary vessels, hence increasing coronary blood flow. However,
maximum exercise levels are often required for sufficient
vasodilation, and exercise capacity varies greatly among patients.
Many patients absolutely cannot exercise to any satisfactory level,
due to peripheral vascular disease, medications, poor patient
motivation, and a variety of other coexisting conditions.
Therefore, exercise may not always be an option.
[0005] The compound adenosine, having the formula
C.sub.10H.sub.13N.sub.5O.sub.4, is known to be highly efficacious
as a pharmacologic stress agent for myocardial imaging in patients
which are unable to exercise adequately. This compound has
consistently produced maximum vasodilation of coronary arteries,
with relatively minimal side effects. Adenosine is typically
administered intravenously to a patient at rest, and its
pharmacological action then mimics some degree of physical
assertion. The short half-life of adenosine is responsible for its
short-acting pharmacological effects, making it extremely useful
for diagnostic evaluation and risk assessment in coronary artery
disease. The attending physician can quickly image the diseased
coronary area, and thereafter the adenosine and any adjunct
compounds are broken down or evacuated from the body.
[0006] Other adenosine-based analogs and derivatives have now shown
great potential as possible coronary vasodilators for use in
medical imaging. Many of these compounds have been set forth and
identified in U.S. Pat. No. 6,232,297. This patent sets forth a new
class of 2-alkynyladenosine derivatives.
[0007] Unfortunately, many adenosine derivatives can be very
difficult to solubilize in aqueous media. There are also long-range
stability issues associated with adenosine-based formulations. To
address this issue, the skilled artisan has often turned to
solvents like glycerol, propylene glycol and other polar additives
when preparing injection solutions. Alternatively,
.beta.-cyclodextrin, because of its unique donut-shape, has been
shown to form inclusion complexes with sparingly soluble and
unstable drugs. The action of .beta.-cyclodextrin significantly
stabilizes and increases the water-solubility of many
pharmacological compounds.
[0008] U.S. Pat. No. 6,407,079 describes many .beta.-cyclodextrin
derivatives which are set forth as being particularly useful as
complex forming agents to solubilize and stabilize active
compounds. These include hydroxyethyl, hydroxypropyl and
dihydroxypropyl ether, their corresponding mixed ethers, and
further mixed ethers with methyl or ethyl groups, such as
methyl-hydroxyethyl, methyl-hydroxypropyl, ethyl-hydroxyethyl and
ethyl-hydroxypropyl ether of .beta.-cyclodextrin.
[0009] However, stability issues may still persist with one or more
of these compounds. What is therefore needed in the art is an
improved composition containing one or more adenosine derivatives,
together with a suitable solvent, that is highly useful in
myocardial perfusion imaging, and is also storage stable for
extended periods. Also needed in the art is a method for enhancing
cardiovascular imaging by administering an improved cardiovascular
stress formulation to a patient.
SUMMARY OF THE INVENTION
[0010] The invention in a first embodiment is directed to a stable
composition useful for myocardial perfusion imaging, comprising one
or more 2-alkynyladenosine derivatives, and a solvent consisting
essentially of water and hydroxypropyl-.beta.-cyclodextrin (which
may also be referred to herein as
hydroxypropylether-.beta.-cyclodextrin).
[0011] In a further embodiment, there is provided a method of
inducing cardiovascular stress for medical imaging purposes, which
involves administering to a patient a pharmacologic vasodilation
formulation, comprising one or more adenosine analogs, a solvent
consisting essentially of water and
hydroxypropyl-.beta.-cyclodextrin, and a buffer.
[0012] More specifically, the invention provides a stable,
adenosine-analog based composition, comprising: [0013] (a) an
adenosine derivative, which is methyl
trans-4-[3-[6-amino-9-(N-ethyl-.beta.-ribofuranosyluronamide)-9H-purin-2--
yl]prop-2-ynyl]cyclohexane carboxylate or a pharmaceutically
acceptable salt thereof; [0014] (b) a solvent consisting
essentially of water and hydroxypropyl-.beta.-cyclodextrin; [0015]
(c) sodium citrate; and [0016] (d) citric acid.
[0017] In addition, the invention includes a kit useful for
cardiovascular stress testing, containing as components one or more
2-alkynyladenosine derivatives, and a solvent consisting
essentially of water and hydroxypropyl-.beta.-cyclodextrin.
[0018] The present invention is directed to these, as well as other
important ends, hereinafter described.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0019] The adenosine analogs or derivatives which are useful as
part of the invention are set forth in U.S. Pat. No. 6,232,297,
which is incorporated in its entirety herein by reference.
Preferred are 2-alkynyladenosine derivatives. Of these, those which
are substituted at the ethyne position by substituted cycloalkyl
moieties are more preferred. Even more desirably, the riboside
residue at the 5'-position ("X" below) is substituted by an
N-alkyl- (or cycloalkyl) carboxyamino ("aminocarbonyl") moiety.
[0020] In particular, the compounds of the invention have the
following general formula (1):
##STR00001##
[0021] wherein
[0022] each R is individually hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.7 cycloalkyl, phenyl or
phenyl(C.sub.1-C.sub.3)-alkyl;
[0023] X is --CH.sub.2OH, --CO.sub.2R.sup.2, --OC(O)R.sup.2,
CH.sub.2OC(O)R.sup.2 or C(O)NR.sup.3R.sup.4;
[0024] each of R.sup.2, R.sup.3 and R.sup.4 is individually H,
C.sub.1-6alkyl, or C.sub.1-6-alkyl substituted with 1-3
C.sub.1-6-alkoxy, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-6-alkylthio,
halogen, hydroxy, amino, mono(C.sub.1-6-alkyl)amino,
di(C.sub.1-6-alkyl)amino, or C.sub.6-10-aryl,
[0025] wherein aryl may be substituted with 1-3 halogen,
C.sub.1-6-alkyl, hydroxy, amino, mono(C.sub.1-6-alkyl)amino, or
di(C.sub.1-6-alkyl)amino; C(,-O-aryl; or C.sub.6-10-aryl
substituted with 1-3 halogen, hydroxy, amino,
mono(C.sub.1-6-alkyl)amino, di(C.sub.1-6-alkyl)amino or
C.sub.1-6-alkyl;
[0026] R.sup.1 is (X-(Z)-).sub.n
[(C.sub.3-C.sub.10)cycloalkyl]-(Z')-, wherein Z and Z' are
individually (C.sub.1-C.sub.6)alkyl, optionally interrupted by 1-3
S or nonperoxide O, or are absent; and,
[0027] n is 1-3; or a pharmaceutically acceptable salt thereof.
[0028] Of the foregoing, particularly preferred are compounds
wherein 5'-X is CH.sub.2OH or C(O)NR.sup.3R.sup.4. More preferred
is the --C(O)NR.sup.3R.sup.4 moiety. Z' is preferably --CH.sub.2 or
CH.sub.2--CH.sub.2. C.sub.3-C.sub.10 cycloalkyl is preferably
cyclohexyl or cyclopentyl. X is preferably C.sub.1-C.sub.4
alkoxycarbonyl, C(O)R.sup.3R.sup.4 or acetoxymethyl.
[0029] More highly preferred compounds useful as part of the
invention include those of formula (I) above wherein each R is H, X
is ethylaminocarbonyl and R.sup.1 is 4-carboxycyclohexylmethyl,
R.sup.1 is 4-methoxycarbonylcyclohexylmethyl or R.sup.1 is
4-acetoxymnethylacyclohexylmethyl. These are set forth below:
##STR00002##
[0030] wherein, acid, X.dbd.H and ester, X=methyl.
[0031] Particularly useful as part of the invention is the compound
identified above as methyl
trans-4-[3-[6-amino-9-(N-ethyl-.beta.-D-ribofuranosyluronamide)-9H-purin--
2-yl]prop-2-ynyl]cyclohexane carboxylate or a pharmaceutically
acceptable salt thereof.
[0032] One or more of the adenosine analogs described above
typically comprise about 0.001 to 10% w/v of the composition of the
invention, more preferably about 0.005 to 1% w/v of the final
formulation. It is preferred that the adenosine derivative be
present in an amount within the range of about 25 to 150 .mu.g/mL
of the final formulation, and even more desirably about 50 to 125
.mu.g/mL. Described yet another way, the adenosine derivatives
herein utilized can be included in an amount to deliver a dose not
exceeding about 5 mcg/kg of body weight, more preferably not
exceeding about 2 mcg/kg of body weight. However, it is expected
that the final amount of adenosine-based compound may be optimized
by the medical practitioner so as to suit the particular needs of a
patient.
[0033] Further included as part of the invention, with one or more
of the adenosine derivatives described above, is a solvent. The
solvent is preferably aqueous-based. More preferably, the solvent
contains water and the inclusion forming compound
hydroxypropyl-.beta.-cyclodextrin, which may also be referred to as
hydroxypropylether-.beta.-cyclodextrin. This compound has been
described in U.S. Pat. No. 6,407,079, which is incorporated herein
by reference. However, it has now been shown that of the
substituted .beta.-cyclodextrins, hydroxypropyl-.beta.-cyclodextrin
is especially efficacious in solubilizing and stabilizing the
adenosine derivatives. In particular,
hydroxypropyl-.beta.-cyclodextrin is preferred over
hydroxyethyl-.beta.-cyclodextrin (also referred to as
hydroxyethylether-.beta.-cyclodextrin), as well as other
substituted .beta.-cyclodextrins, in particular other substituted
ether .beta.-cyclodextrins. Hydroxypropyl-.beta.-cyclodextrin is
also preferred over other solvents such as unsubstituted
.beta.-cyclodextrin, .delta.-cyclodextrin, propylene glycol, and
Captisol (another substituted .beta.-cyclodextrin). Thus, it is
highly preferred that no other solubility enhancers other than
hydroxypropyl-.beta.-cyclodextrin, in particular other
.beta.-cyclodextrins, be included in the final composition, other
than residual or trace amounts that might remain after normal
processing.
[0034] Examples of the concentration of
hydroxypropyl-.beta.-cyclodextrin include being within the range of
about 0.1-10% w/v, about 0.5 to 2% w/v, and about 1% w/v of the
final formulation. One example of the molar ratio of the adenosine
derivative to hydroxypropyl-.beta.-cyclodextrin is within the range
of about 1:30 to 1:150.
[0035] Water can comprise the remainder of the solvent, and by
extension, the remainder of the final formulation, but for optional
additional excipients.
[0036] Certain excipients, such as buffers, for example, also may
be included in the composition of the invention. Buffers act as pH
control agents, and can include such compounds as citric acid,
sodium citrate, or both. Other buffers available to the skilled
artisan may also be utilized. Other excipients such as
preservatives and rheology agents, for example, may also be
included, if desired. The additional excipient(s) together can
comprise from about 0.001 to 1% w/v of the final composition.
[0037] In another embodiment, hydroxyethyl-.beta.-cyclodextrin is
absent from the composition of the invention. In another
embodiment, any other .beta.-cyclodextrin is absent from the
composition of the invention. In another embodiment, any other
solvent is absent from the composition of the invention.
[0038] To prepare the composition of the invention, the adenosine
derivative may be admixed with the solvent, and any additional
excipients. The solvent may be first prepared by admixing the water
and hydroxypropyl-.beta.-cyclodextrin. A dosage form may be
prepared as set forth in the art, such as a sealed bolus, vial or
syringe using materials that are readily available. The composition
of the invention may also be assembled into a ready-to-use kit,
with one or more dosage units contained therein.
[0039] The composition of the invention is highly storage stable
for extended periods. Preferably, in sealed form, the composition
can remain efficacious for up to at least about three (3) months,
and more preferably up to about six (6) months. It is desirable
that the composition remain storage stable for periods of up to
about one (1) year, and even more desirably up to at least about
two (2) years, or even longer.
[0040] Further provided as part of the invention is a method of
cardiovascular imaging using a stress-inducing, pharmacologic
agent, comprising administering to a patient a formulation
according to the present invention, containing one or more
adenosine derivatives as heretofore described, together with the
solvent, and any excipients, as also described. Preferably, the
composition is administered intravenously by a skilled practitioner
such as a doctor, physician's assistant, or nurse practitioner
using procedures established in the art. Other methods of
administration may be contemplated by the skilled artisan. The
composition is administered in a dose and at a rate which will
allow the practitioner to then obtain a readable image of the
myocardial region of interest. The image is obtained using methods
available in the art.
[0041] In a preferred embodiment, the composition of the invention
is administered in a dose which does not exceed about 5 mcg
adenosine derivative per kilogram of patient body weight. More
preferably, the dosage is such that the amount of administered
adenosine derivative does not exceed about 2 mcg/kg. of patient
body weight. Even more desirably, the composition is administered
in a dose of between about 0.05 and 5 mcg/kg of patient body
weight.
EXAMPLES
[0042] The following examples are provided to illustrate various
preferred aspects of the invention, and should not be construed as
limiting the scope thereof:
Example 1
[0043] The following composition was prepared as hereinabove
described:
TABLE-US-00001 Components Amount or Description Methyl
trans-4-[3-[6-amino-9-(N-ethyl-.beta.-D- 100 .mu.g/mL
ribofuranosyluronamide)-9H-purin-2- yl]prop-2-ynyl]cyclohexane
carboxylate Sodium Citrate Buffer 10 mM at pH 4.8 .+-. 0.2
Hydroxypropyl-.beta.- 2% by weight Cyclodextrin (CAS 128446-35-5)
(Hydroxypropyl Betadex [USP]) WFI (water for injection) Q.S.
Headspace Air Fill Volume 3 mL
[0044] After preparation, the above formulation was aluminum
crimp-sealed in a 5 cc tubing vial, and closed with a 20mm serum
stopper. Also prepared was a formulation containing 50 .mu.g/mL of
active substance, together with 1% by weight of
hydroxypropyl-.beta.-cyclodextrin.
Example 2
[0045] The present study established the bioequivalency of the
pharmacokinetic parameters for one formulation according to a
preferred embodiment of the invention versus another formulation in
an anesthetized open chest canine model using the same adenosine
analog. Five female mongrel dogs, 1.5-2 years of age (11-15 kg)
were used. After surgical instrumentation and a stabilization
period, each dog received a bolus intravenous injection of
adenosine (300 .mu.g/kg) as a reference control followed by four
intravenous doses (noncumulative) of Formulation 1 (the invention)
and Formulation 2 (a lyophilized formulation) (two 1 .mu.g/kg doses
of each formulation). Blood samples were collected at 0 (pre-dose),
1, 3, 5, 7, 10, 15 and 30 minutes post-injection of each dose for
determination of plasma levels of the active drug substance
adenosine analog and the carboxylic acid metabolite by LC/MS/MS.
Pharmacokinetic (PK) analysis included C.sub.max, area under the
time-plasma concentration curve (AUC), clearance (CL), volume of
distribution at steady state (V.sub.dss) and terminal ((R), phase)
half-life (t.sub.1/2). Hemodynamic responses, expressed as a
percent change from baseline values, for each dose level included
measurements of coronary blood flow, arterial blood pressure, heart
rate, left ventricular systolic pressure and +dP/di. Bioequivalence
was determined using log transformation of the data. The two
adenosine analog formulations were considered to be bioequivalent
if the 90% confidence interval for the ratio of the formulation
means for AUC of adenosine analog and the carboxylic acid
metabolite was within 0.8 and 1.25.
[0046] The plasma levels of adenosine analog and the carboxylic
acid metabolite of Formulations 1 and 2 had nearly identical
profiles. The 90% confidence intervals for the ratio of AUC
(0-last) for adenosine analog and for the carboxylic acid
metabolite were 1.02 to 1.15 and 0.94 to 1.16, respectively, which
were within the acceptable limits of 0.8 to 1.25 to demonstrate
bioequivalence. Additional pharmacokinetic parameters for adenosine
analog (AUC (0-.infin.), CL, C.sub.max, t.sub.1/2, V.sub.dss) and
the carboxylic metabolite (C.sub.max, t.sub.1/2) also met the
bioequivalence criterion.
[0047] Administration of both Formulations 1 and 2 at 1 .mu.g/kg
caused similar pharmacodynamic changes. There were no significant
differences, respectively, on increase in mean coronary blood flow
(147.5% vs. 160.4%), duration of coronary blood flow increase
.gtoreq.150% of baseline (5.7 vs. 5.0 minutes), decrease in mean
arterial blood pressure (23.3% vs. 23.6%), increase in heart rate
(11.3% vs. 12.2%), increase in left ventricular systolic pressure
(9.0% vs. 6.0%) and increase in +dP/dt (46.3% vs. 45.4%). These
findings are consistent with Formulations 1 and 2 being
equivalent.
[0048] Based on the pharmacokinetic assessment, the results of this
study demonstrated that the Formulations 1 and 2 are bioequivalent
and both are capable of inducing increased coronary blood flow in
the anesthetized open chest dog.
Example 3
[0049] This example illustrates the comparative stability of
adenosine derivative compositions using
hydroxypropyl-.beta.-cyclodextrin as part of the invention, versus
those containing hydroxyethyl-.beta.-cyclodextrin.
[0050] A solution of methyl
trans4-[3-[6-amino-9-(N-ethyl-.beta.-D-ribofuranosyluronamide)-9H-purin-2-
-yl]prop-2-ynyl]cyclohexane carboxylate at 50 .mu.g/mL was prepared
in 10 mM citrate buffer at pH 4.8 with 1% (w/v) of hydroxypropyl-62
-cyclodextrin. A similar solution was prepared except that the 1%
(w/v) hydroxypropyl-.beta.-cyclodextrin was replaced with 1% (w/v)
hydroxyethyl-.beta.-cyclodextrin. Both solutions were stored at
70.degree. C. for a period of fourteen days. The stability of the
adenosine derivative was evaluated over the fourteen day period
using chromatography to measure the increase in the primary
degradation product, which is generated by hydrolysis of the methyl
ester to form the acid by the reaction shown below.
##STR00003##
[0051] A plot of the amount of the acid (% w/w relative to the
adenosine derivative) formed as a function of time (days) is shown
below for the adenosine derivative solutions using either
hydroxypropyl-.beta.-cyclodextrin or
hydroxyethyl-.beta.-cyclodextrin. The plot clearly demonstrates
that the rate of formation of the acid complex is lower when the
stabilizing agent is hydroxypropyl-.beta.-cyclodextrin relative to
hydroxyethyl-.beta.-cyclodextrin. For example, after fourteen days
the amount of acid is 1.5% (w/w) using
hydroxypropyl-.beta.-cyclodextrin and is 1.7% (w/w) using
hydroxyethyl-.beta.-cyclodextrin.
[0052] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appended claims.
* * * * *