U.S. patent application number 12/366931 was filed with the patent office on 2009-09-10 for compositions comprising nebivolol.
This patent application is currently assigned to Mylan Laboratories, Inc.. Invention is credited to Peter Bottini, Eric Davis, John O'Donnell.
Application Number | 20090227646 12/366931 |
Document ID | / |
Family ID | 35449867 |
Filed Date | 2009-09-10 |
United States Patent
Application |
20090227646 |
Kind Code |
A1 |
Davis; Eric ; et
al. |
September 10, 2009 |
Compositions Comprising Nebivolol
Abstract
Nebivolol has been shown to be beneficial in the treatment of
cardiovascular diseases such hypertension, congestive heart
failure, arterial stiffness and endothelial dysfunction. The
present invention features a pharmaceutical composition comprising
nebivolol and at least one other active agent, wherein the at least
one other active agent is a cardiovascular agent.
Inventors: |
Davis; Eric; (Morgantown,
WV) ; O'Donnell; John; (Morgantown, WV) ;
Bottini; Peter; (Morgantown, WV) |
Correspondence
Address: |
FROST BROWN TODD, LLC
2200 PNC CENTER, 201 E. FIFTH STREET
CINCINNATI
OH
45202
US
|
Assignee: |
Mylan Laboratories, Inc.
Morgantown
WV
|
Family ID: |
35449867 |
Appl. No.: |
12/366931 |
Filed: |
February 6, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11141235 |
May 31, 2005 |
|
|
|
12366931 |
|
|
|
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60577423 |
Jun 4, 2004 |
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Current U.S.
Class: |
514/381 |
Current CPC
Class: |
A61K 31/35 20130101;
A61K 31/353 20130101 |
Class at
Publication: |
514/381 |
International
Class: |
A61K 31/41 20060101
A61K031/41; A61P 9/00 20060101 A61P009/00 |
Claims
1-36. (canceled)
37. A composition comprising nebivolol or a pharmaceutically
acceptable salt thereof, and an angiotensin II receptor antagonist
(ARB) selected from the group consisting of olmesartan, valsartan,
losartan, and combinations thereof, and pharmaceutically acceptable
salts thereof.
38. The composition of claim 37, wherein the ARB is selected from
the group consisting of losartan, valsartan, and combinations
thereof, and pharmaceutically acceptable salts thereof.
39. The composition of claim 37, wherein the ARB is losartan or a
pharmaceutically acceptable salt thereof.
40. A method of treating or preventing hypertension in a patient in
need thereof, comprising administering to said patient an effective
amount of nebivolol or a pharmaceutically acceptable salt thereof,
and an angiotensin II receptor antagonist (ARB) selected from the
group consisting of olmesartan, valsartan, losartan, and
combinations thereof, and pharmaceutically acceptable salts
thereof.
41. The method of claim 40, wherein the ARB is selected from the
group consisting of losartan, valsartan, and combinations thereof,
and pharmaceutically acceptable salts thereof.
42. The method of claim 40, wherein the ARB is losartan or a
pharmaceutically acceptable salt thereof.
43. A method of treating or preventing cardiovascular disease in a
patient in need thereof, comprising administering to said patient
an effective amount of nebivolol or a pharmaceutically acceptable
salt thereof, and an angiotensin II receptor antagonist (ARB)
selected from the group consisting of olmesartan, valsartan,
losartan, and combinations thereof, and pharmaceutically acceptable
salts thereof.
44. The method of claim 43, wherein the ARB is selected from the
group consisting of losartan, valsartan, and combinations thereof,
and pharmaceutically acceptable salts thereof.
45. The method of claim 43, wherein the ARB is losartan or a
pharmaceutically acceptable salt thereof.
Description
[0001] This application is a divisional of U.S. Non-Provisional
patent application Ser. No. 11/141,235, filed May 31, 2005, which
is based on and claims priority from U.S. Provisional Patent
Application Ser. No. 60/577,423, Eric Davis, John O'Donnell, Peter
Bottini, filed Jun. 4, 2004; the disclosures of both are hereby
incorporated by reference in their entirety.
TECHNICAL FIELD
[0002] This invention relates to compositions comprising nebivolol
and one or more other active agent. More particularly, this
invention relates to compositions comprising nebivolol and one or
more cardiovascular agents for the treatment and/or prevention of
cardiovascular diseases.
BACKGROUND OF THE INVENTION
[0003] Hypertension is a major health concern in the US.
Approximately 50 million Americans have elevated blood pressure
defined as a systolic blood pressure (SBP).gtoreq.140 mmHg or a
diastolic blood pressure (DBP).gtoreq.90 mmHg. In addition,
individuals with blood pressure of 120/80 mmHg or higher are at
increased risk of developing hypertension and are considered to be
in a "pre-hypertension" state. Severity of hypertension is
currently classified by stage, with Stage 1 hypertension spanning
blood pressure ranges from 140/90 to 159/99 mmHg and Stage 2
including blood pressures .gtoreq.160/100 mmHg.
[0004] Onset of hypertension (diastolic alone or in combination
with systolic) typically occurs between 25 and 55 years of age. The
risk of developing hypertension increases more dramatically with
increasing age. According to the CDC, 68.3% of men aged 65-74 have
hypertension in the U.S. (Health United States, 2003, CDC/National
Center for Health Statistics) and 70.7% of men aged over 75 have
hypertension in the U.S. (Health United States, 2003, CDC/National
Center for Health Statistics). In addition, 73.4% of women aged
65-74 have hypertension in the US (Health United States, 2003,
CDC/National Center for Health Statistics) and 84.9% of women aged
over 75 have hypertension in the US (Health United States, 2003,
CDC/National Center for Health Statistics).
[0005] Pharmaceutical formulations that stimulate, agonize, or
potentiate endothelial nitric oxide production, particularly
formulations that produce increased nitric oxide levels in African
Americans, are needed.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention features a
pharmaceutical composition comprising nebivolol and at least one
other active agent. In a further embodiment, at least one of the
active agents is a cardiovascular agent. In a further embodiment,
the at least one cardiovascular agent is selected from the group
consisting of ACE inhibitors (angiotensin II converting enzyme
inhibitors), ARB's (angiotensin II receptor antagonists),
adrenergic blockers, adrenergic agonists, agents for
pheochromocytoma, antiarrhythmics, antiplatelet agents,
anticoagulants, antihypertensives, antilipemic agents,
antidiabetics, antiinflammatory agents, calcium channel blockers,
CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors,
diuretics, endothelin receptor antagonists, HMG Co-A reductase
inhibitors, inotropic agents, rennin inhibitors, vasodialators,
vasopressors, AGE crosslink breakers (advanced glycosylation
end-product crosslink breakers, such as alagebrium, see U.S. Pat.
No. 6,458,819), and AGE formation inhibitors (advanced
glycosylation end-product formation inhibitors, such as
pimagedine), and mixtures thereof. In one embodiment, the other
cardiovascular agent is an ACE inhibitor or an ARB. In a further
embodiment, the other cardiovascular agent includes an ACE
inhibitor and an ARB. In a further embodiment, the ACE inhibitor is
selected from the group consisting of: alacepril, benazepril,
captopril, ceronapril, cilazapril, delapril, enalapril,
enalaprilat, fosinopril, imidapril, lisinopril, perindopril,
quinapril, ramipril, ramiprilat, spirapril, temocapril,
trandolapril. In a further embodiment, the ACE inhibitor is
enalapril, ramipril, or ramiprilat. In a further embodiment, the
other cardiovascular agent is an ARB selected from the group
consisting of candesartan, eprosartan, irbesartan, losartan,
valsartan.
[0007] In a further embodiment, the pharmaceutical composition
comprises an amount of nebivolol in the range of between about
0.125 mg and about 40 mg. In a further embodiment, the amount of an
ACE inhibitor may be in the range of between about 0.5 mg to about
80 mg, and/or the amount of ARB may be in the range of between
about 1 mg and about 1200 mg.
[0008] In a further embodiment, the pharmaceutical composition
comprises nebivolol and only one other active agent. In a further
embodiment, the pharmaceutical composition comprises nebivolol and
only one cardiovascular agent. In a further embodiment, the
cardiovascular agent is selected from the group consisting of ACE
inhibitors (angiotensin II converting enzyme inhibitors), ARB's
(angiotensin II receptor antagonists), adrenergic blockers,
adrenergic agonists, agents for pheochromocytoma, anti-anginal
agents, antiarrhythmics, antiplatelet agents, anticoagulants,
antihypertensives, antilipemic agents, antidiabetics,
antiinflammatory agents, calcium channel blockers, CETP inhibitors,
COX-2 inhibitors, direct thrombin inhibitors, diuretics, endothelin
receptor antagonists, HMG Co-A reductase inhibitors, inotropic
agents, rennin inhibitors, vasodialators, vasopressors, AGE
crosslink breakers (advanced glycosylation end-product crosslink
breakers, such as alagebrium, see U.S. Pat. No. 6,458,819), and AGE
formation inhibitors (advanced glycosylation end-product formation
inhibitors, such as pimagedine). In a further embodiment, the
active agent is an ACE inhibitor or and ARB.
[0009] In another aspect, the present invention features a method
of treating a subject for a cardiovascular disorder comprising
administering to the subject an effective amount of nebivolol in
combination with at least one other cardiovascular agent. In a
further embodiment, the cardiovascular disorder is selected from
the group consisting of atherosclerosis, hypertension, diabetes
mellitus, hyperhomocysteinemia, heart failure, and renal
failure.
[0010] In another aspect, the present invention features a method
of preventing a cardiovascular disorder comprising administration
to a subject an effective amount of nebivolol in combination with
an effective amount of at least one other cardiovascular agent. In
a further embodiment, the cardiovascular disorder is selected from
the group consisting of congestive heart failure, hypertension,
pulmonary hypertension, myocardial and cerebral infarctions,
atherosclerosis, atherogenesis, thrombosis, ischemic heart disease,
post-angioplasty restenosis, coronary artery diseases, renal
failure, stable, unstable and variant (Prinzmetal) angina, cardiac
edema, renal insufficiency, nephrotic edema, hepatic edema, stroke,
transient ischemic attacks, cerebrovascular accidents, restenosis,
controlling blood pressure in hypertension, platelet adhesion,
platelet aggregation, smooth muscle cell proliferation, pulmonary
edema, and vascular complications associated with the use of
medical devices.
[0011] In another aspect, the present invention features a kit
comprising an effective amount of nebivolol in combination with an
effective amount of another cardiovascular agent.
[0012] Even though nebivolol has .beta.-blocking properties,
nebivolol is different from other classic .beta.-blockers in that
it is highly selective to the .beta.1 adrenergic receptors and also
has vasodilating effects related to its effect on endothelial
nitric oxide. It is believed that nebivolol increases the levels of
nitric oxide within the vascular endothelium through the
L-arginine-nitric oxide pathway and has been shown to improve
endothelial dysfunction and improve compliance of blood vessels.
Nebivolol has also been shown to have antioxidant characteristics
which are favorable to the normal functioning of the vascular
endothelium. These characteristics make nebivolol an effective
antihypertensive agent with favorable effects on the vascular
endothelium and cardiovascular system. Nebivolol has been shown to
be beneficial in the treatment of cardiovascular diseases such as
hypertension, congestive heart failure, arterial stiffness and
endothelial dysfunction. In part, the present invention features a
composition comprising nebivolol and another cardiovascular agent
that is believed to work via a different mechanism.
[0013] These embodiments of the present invention, other
embodiments, and their features and characteristics, will be
apparent from the description, drawings and claims that follow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 depicts a comparison of NO release from Black and
White donor endothelial cells after chronic treatment with
ramprilat followed by treatment with nebivolol (1 .mu.M).
[0015] FIG. 2 depicts a comparison of the increase in NO release
from Black and White donor endothelial cells after chronic
treatment with ramiprilat followed by treatment with nebivolol (1
.mu.M).
[0016] FIG. 3 depicts comparison of NO release from Black and White
donor endothelial cells after chronic treatment with enalapril
followed by treatment with nebivolol (1 .mu.M).
[0017] FIG. 4 depicts a comparison of the increase in NO release
from Black and White donor endothelial cells after chronic
treatment with enalapril followed by treatment with nebivolol (1
.mu.M).
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0018] For convenience, before further description of the present
invention, certain terms employed in the specification, examples
and appended claims are collected here. These definitions should be
read in light of the remainder of the disclosure and understood as
by a person of skill in the art. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
commonly understood by a person of ordinary skill in the art.
[0019] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0020] The phrase "angiotensin converting enzyme inhibitor" or "ACE
inhibitor" as used herein refers to a compound that inhibits any
enzyme from converting angiotensin to any other form.
[0021] The phrase "angiotensin II receptor antagonist" or "ARB"
refers to a compound that binds to a receptor site on angiotensin
II but does not cause any physiological changes unless another
receptor ligand is present.
[0022] The term "antagonist" is art-recognized and refers to a
compound that binds to a receptor site, but does not cause a
physiological change unless another receptor ligand is present.
[0023] The term "bioavailable" is art-recognized and refers to a
form of the subject invention that allows for it, or a portion of
the amount administered, to be absorbed by, incorporated to, or
otherwise physiologically available to a subject or patient to whom
it is administered.
[0024] The phrase "cardiovascular agent" or "cardiovascular drug"
refers to a therapeutic compound that is useful for treating or
preventing a cardiovascular disease. Non-limiting examples of
suitable cardiovascular agents include ACE inhibitors (angiotensin
II converting enzyme inhibitors), ARB's (angiotensin II receptor
antagonists), adrenergic blockers, adrenergic agonists, agents for
pheochromocytoma, antianginal agents, antiarrhythmics, antiplatelet
agents, anticoagulants, antihypertensives, antilipemic agents,
antidiabetics, antiinflammatory agents, calcium channel blockers,
CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors,
diuretics, endothelin receptor antagonists, HMG Co-A reductase
inhibitors, inotropic agents, rennin inhibitors, vasodialators,
vasopressors, AGE crosslink breakers (advanced glycosylation
end-product crosslink breakers, such as alagebrium, see U.S. Pat.
No. 6,458,819), and AGE formation inhibitors (advanced
glycosylation end-product formation inhibitors, such as
pimagedine), and combinations thereof.
[0025] Cardiovascular disease or disorder refers to any
cardiovascular disease or disorder known in the art, including, but
not limited to, wherein the cardiovascular disease is selected from
the group consisting of congestive heart failure, hypertension,
pulmonary hypertension, myocardial and cerebral infarctions,
atherosclerosis, atherogenesis, thrombosis, ischemic heart disease,
post-angioplasty restenosis, coronary artery diseases, renal
failure, stable, unstable and variant (Prinzmetal) angina, cardiac
edema, renal insufficiency, nephrotic edema, hepatic edema, stroke,
transient ischemic attacks, cerebrovascular accidents, restenosis,
controlling blood pressure in hypertension, platelet adhesion,
platelet aggregation, smooth muscle cell proliferation, pulmonary
edema, and vascular complications associated with the use of
medical devices.
[0026] The term "combination" refers to two or more different
active agents which are administered at roughly about the same time
(for example, where the active agents are in a single
pharmaceutical preparation) or at different times (for example, one
agent is administered to the subject before the other).
[0027] The terms "drug," "pharmaceutically active agent,"
"bioactive agent," "therapeutic agent," and "active agent" may be
used interchangeably and refer to a substance, such as a chemical
compound or complex, that has a measurable beneficial physiological
effect on the body, such as a therapeutic effect in treatment of a
disease or disorder, when administered in an effective amount.
Further, when these terms are used, or when a particular active
agent is specifically identified by name or category, it is
understood that such recitation is intended to include the active
agent per se, as well as pharmaceutically acceptable,
pharmacologically active derivatives thereof, or compounds
significantly related thereto, including without limitation, salts,
pharmaceutically acceptable salts, N-oxides, prodrugs, active
metabolites, isomers, fragments, analogs, solvates hydrates,
radioisotopes, etc.
[0028] The phrase "effective amount" refers to that amount of a
substance that produces some desired local or systemic effect at a
reasonable benefit/risk ratio applicable to any treatment. The
effective amount of such substance will vary depending upon the
subject and disease condition being treated, the weight and age of
the subject, the severity of the disease condition, the manner of
administration and the like, which can readily be determined by one
of ordinary skill in the art.
[0029] "Endothelial dysfunction" refers to the impaired ability of
in any physiological processes carried out by the endothelium, in
particular, production of nitric oxide regardless of cause. It may
be evaluated by, such as, for example, invasive techniques, such
as, for example, coronary artery reactivity to acetylcholine or
methacholine, and the like, or by noninvasive techniques, such as,
for example, blood flow measurements, brachial artery flow dilation
using cuff occlusion of the arm above or below the elbow, brachial
artery ultrasonography, imaging techniques, measurement of
circulating biomarkers, such as, asymmetric dimethylarginine
(ADMA), and the like. For the latter measurement the
endothelial-dependent flow-mediated dialation will be lower in
patients diagnosed with an endothelial dysfunction.
[0030] The phrase "endothelial nitric oxide synthase" or "eNOS"
refers to enzymes that produce nitric oxide
[0031] The phrase "nebivolol composition" refers to a composition
comprising nebivolol. Nebivolol is a mixture of d and l isomers of
.alpha.,.alpha.'-[iminobismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopy-
ran-2-methanol]. The composition may include at least one other
cardiovascular agent or at least one pharmaceutically acceptable
carrier or both.
A "patient," "subject" or "host" may be a human or non-human
animal.
[0032] The term "pharmaceutically acceptable salts" is
art-recognized and refers to the relatively non-toxic, inorganic
and organic acid addition salts of compounds, including, for
example, those contained in compositions of the present
invention.
[0033] The term "pharmaceutically acceptable carrier" is
art-recognized and refers to a pharmaceutically-acceptable
material, composition or vehicle, such as a liquid or solid filler,
diluent, excipient, solvent or encapsulating material, involved in
carrying or transporting any subject composition or component
thereof from one organ, or portion of the body, to another organ,
or portion of the body. Each carrier must be acceptable in the
sense of being compatible with the subject composition and its
components and not injurious to the patient. Some examples of
materials which may serve as pharmaceutically acceptable excipients
include: (1) sugars, such as lactose, glucose and sucrose; (2)
starches, such as corn starch and potato starch; (3) cellulose, and
its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt;
(6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil;
(10) glycols, such as propylene glycol; (11) polyols, such as
glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,
such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering
agents, such as magnesium hydroxide and aluminum hydroxide; (15)
alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)
IV fluids, including but not limited to Ringer's solution, 5%
dextrose in water, and half normalsaline; (19) ethyl alcohol; (20)
phosphate buffer solutions; and (21) other non-toxic compatible
substances employed in pharmaceutical formulations.
[0034] The term "prophylactic" or "therapeutic" treatment is
art-recognized and refers to administration to the host of one or
more of the subject compositions. If it is administered prior to
clinical manifestation of the unwanted condition (e.g., disease or
other unwanted state of the host animal) then the treatment is
prophylactic, i.e., it protects the host against developing the
unwanted condition, whereas if administered after manifestation of
the unwanted condition, the treatment is therapeutic (i.e., it is
intended to diminish, ameliorate or maintain the existing unwanted
condition or side effects therefrom).
[0035] The term "structure-activity relationship" or "(SAR)" is
art-recognized and refers to the way in which altering the
molecular structure of a drug or other compound alters its
interaction with a receptor, enzyme, nucleic acid or other target
and the like.
[0036] It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, or other
reaction.
[0037] The term "substituted" is also contemplated to include all
permissible substituents of organic compounds. In a broad aspect,
the permissible substituents include acyclic and cyclic, branched
and unbranched, carbocyclic and heterocyclic, aromatic and
nonaromatic substituents of organic compounds. Illustrative
substituents include, for example, those described herein above.
The permissible substituents may be one or more and the same or
different for appropriate organic compounds. For purposes of this
invention, the heteroatoms such as nitrogen may have hydrogen
substituents and/or any permissible substituents of organic
compounds described herein which satisfy the valences of the
heteroatoms. This invention is not intended to be limited in any
manner by the permissible substituents of organic compounds.
[0038] The term "synthetic" is art-recognized and refers to
production by in vitro chemical or enzymatic synthesis.
[0039] The phrase "therapeutic effect" is art-recognized and refers
to a local or systemic effect in animals, particularly mammals, and
more particularly humans caused by a pharmacologically active
substance. The term thus means any substance intended for use in
the diagnosis, cure, mitigation, treatment or prevention of disease
or in the enhancement of desirable physical or mental development
and/or conditions in an animal or human. The phrase
"therapeutically-effective amount" means that amount of such a
substance that produces some desired local or systemic effect at a
reasonable benefit/risk ratio applicable to any treatment. The
therapeutically effective amount of such substance will vary
depending upon the subject and disease condition being treated, the
weight and age of the subject, the severity of the disease
condition, the manner of administration and the like, which can
readily be determined by one of ordinary skill in the art.
[0040] The term "treating" is art-recognized and refers to curing
as well as ameliorating at least one symptom of any condition or
disease.
Nebivolol
[0041] Nebivolol is a .beta.-receptor blocking drug that is a
mixture of d- and l-enantiomers, of which d-nebivolol is a highly
selective .beta..sub.1-receptor antagonist.
##STR00001##
[0042] In addition to its .beta.-receptor blocking properties,
nebivolol has been shown to cause endothelium-dependent
vasodilation in both normotensive and hypertensive subjects.
Cockcroft J R, Chowienczyk P J, Brett S E, Chen C P, Dupont A G,
Nueten L V, Wooding S J, Ritter J M., Journal of Pharmacology and
Experimental Therapeutics. 1995; 274:1067-1071; Tzemos N, Lim P O,
MacDonald T M., Circulation, 2001; 104:511-514; Broeders M A,
Doevendans P A, Bekkers B C, Bronsaer R, van Gorsel E, Heemskerk J
W, Egbrink M G, van Breda E, Reneman R S, van Der Zee R.,
Circulation. 2000; 102:677-684. In experimental models, nebivolol
has been demonstrated to stimulate NO release through
.beta..sub.2-adrenergic receptor-mediated NO production and/or ATP
efflux with consequent stimulation of P2Y-purinoceptor-mediated NO
release. Broeders M A, Doevendans P A, Bekkers B C, Bronsaer R, van
Gorsel E, Heemskerk J W, Egbrink M G, van Breda E, Reneman R S, van
Der Zee R., Circulation, 2000; 102:677-684; Kalinowski L, Dobrucki
L W, Szczepanska-Konkel M, Jankowski M, Martyniec L, Angielski S,
Malinski T., Circulation, 2003; 107:2747-2752. It has also been
reported that nebivolol inhibits NO synthase uncoupling and
produces systemic antioxidant effects. Mollnau H, Schulz E, Daiber
A, Baldus S, Oelze M, August M, Wendt M, Walter U, Geiger C,
Agrawal R, Kleschyov A L, Meinertz T, Thomas Munzel T.,
Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;
23:615-621; Troost R, Schwedhelm E, Rojczyk S, Tsikas D, Frolich J
C., British Journal of Clinical Pharmacology, 2000; 50:377-379.
Compositions Comprising Nebivolol
[0043] In part, the present invention features compositions
comprising nebivolol and at least one other active agent, wherein
the at least one other active agent is a cardiovascular agent. The
amount of each cardiovascular agent present in the compositions may
vary depending on a number of variables such as age, weight,
gender, and health related issues. In general, the dosage of the
cardiovascular agents will generally be in the range of about 0.01
ng to about 10 g per kg body weight, specifically in the range of
about 1 ng to about 0.1 g per kg, and more specifically in the
range of about 100 ng to about 10 mg per kg. In another embodiment,
the amount of nebivolol in the compositions of the present
invention may be anywhere from about 0.125 mg to about 40 mg. In
one example, when the other cardiovascular agent is an ACE
inhibitor, the amount of the ACE inhibitor may be anywhere from 0.5
mg to about 80 mg. When the other cardiovascular agent is an ARB,
the amount of ARB may be anywhere from about 1 mg to about 1200 mg.
The amount of the other cardiovascular agent will depend in part on
the particular cardiovascular agent used.
[0044] In addition to ACE inhibitors and ARBs, additional
cardiovascular agents include, but are not limited to adrenergic
blockers, adrenergic agonists, agents for pheochromocytoma,
antianginal agents, antiarrhythmics, antiplatelet agents,
anticoagulants, antihypertensives, antilipemic agents,
antidiabetics, antiinflammatory agents, calcium channel blockers,
CETP inhibitors, COX-2 inhibitors, direct thrombin inhibitors,
diuretics, endothelin receptor antagonists, HMG Co-A reductase
inhibitors, inotropic agents, rennin inhibitors, vasodialators,
vasopressors, AGE crosslink breakers (advanced glycosylation
end-product crosslink breakers, such as alagebrium, see U.S. Pat.
No. 6,458,819), and AGE formation inhibitors (advanced
glycosylation end-product formation inhibitors, such as
pimagedine). Cardiovascular agents falling within these general
categories are exemplified by the following:
"Angiotensin I Converting Enzymes (ACE's) and Angiotensin II
Receptor Antagonists (ARB's)"
[0045] "Angiotensin II receptor antagonists" (ARB's) are compounds
which interfere with the activity of angiotensin II by binding to
angiotensin II receptors and interfering with its activity.
Angiotensin I and angiotensin II are synthesized by the enzymatic
renin-angiotensin pathway. The synthetic process is initiated when
the enzyme renin acts on angiotensinogen, a pseudoglobulin in blood
plasma, to produce the decapeptide angiotensin I. Angiotensin I is
converted by angiotensin converting enzyme (ACE) to angiotensin II
(angiotensin-[1-8] octapeptide). The latter is an active pressor
substance which has been implicated as a causative agent in several
forms of hypertension in various mammalian species, e.g.,
humans.
[0046] Angiotensin II receptor antagonists (ARB's) are well known
and include peptide compounds and non-peptide compounds. Most
angiotensin II receptor antagonists are slightly modified congeners
in which agonist activity is attenuated by replacement of
phenylalanine in position 8 with some other amino acid; stability
can be enhanced by other replacements that slow degeneration in
vivo.
[0047] Examples of angiotensin II receptor antagonists include:
peptidic compounds (e.g., saralasin and related analogs);
N-substituted imidazole-2-one (U.S. Pat. No. 5,087,634); imidazole
acetate derivatives including
2-N-butyl-4-chloro-1-(2-chlorobenzile) imidazole-5-acetic acid (see
Long et al., J. Pharmacol. Exp. Ther. 247(1), 1-7 (1988));
4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid and
analog derivatives (U.S. Pat. No. 4,816,463); N2-tetrazole
beta-glucuronide analogs (U.S. Pat. No. 5,085,992); substituted
pyrroles, pyrazoles, and tryazoles (U.S. Pat. No. 5,081,127);
phenol and heterocyclic derivatives such as 1,3-imidazoles (U.S.
Pat. No. 5,073,566); imidazo-fused 7-member ring heterocycles (U.S.
Pat. No. 5,064,825); peptides (e.g., U.S. Pat. No. 4,772,684);
antibodies to angiotensin II (e.g., U.S. Pat. No. 4,302,386); and
aralkyl imidazole compounds such as biphenyl-methyl substituted
imidazoles (e.g., EP 253,310, Jan. 20, 1988); ES8891
(N-morpholinoacetyl-(-1-naphthyl)-L-alanyl-(4,
thiazolyl)-L-alanyl(35,45)-4-amino-3-hydroxy-5-cyclo-hexapentanoyl-N-hexy-
lamide, Sankyo Company, Ltd., Tokyo, Japan); SKF108566
(E-alpha-2-[2-butyl-1-(carboxy
phenyl)methyl]1H-imidazole-5-yl[methylane]-2-thiophenepropanoic
acid, Smith Kline Beecham Pharmaceuticals, Pa.); Losartan
(DUP753/MK954, DuPont Merck Pharmaceutical Company); Remikirin
(RO42-5892, F. Hoffman LaRoche A G); A.sub.2 agonists (Marion
Merrill Dow) and certain non-peptide heterocycles (G. D. Searle and
Company). Other non-limiting examples of ARBs include candesartan,
eprosartan, irbesartan, losartan, and valsartan. Other ARBs may be
identified using standard assaying techniques known to one of
ordinary skill in the art.
[0048] "Angiotensin converting enzyme" (ACE) is an enzyme which
catalyzes the conversion of angiotensin I to angiotensin II. ACE
inhibitors include amino acids and derivatives thereof, peptides,
including di- and tri-peptides and antibodies to ACE which
intervene in the renin-angiotensin system by inhibiting the
activity of ACE thereby reducing or eliminating the formation of
pressor substance angiotensin II. ACE inhibitors have been used
medically to treat hypertension, congestive heart failure,
myocardial infarction and renal disease. Classes of compounds known
to be useful as ACE inhibitors include acylmercapto and
mercaptoalkanoyl prolines such as captopril (U.S. Pat. No.
4,105,776) and zofenopril (U.S. Pat. No. 4,316,906), carboxyalkyl
dipeptides such as enalapril (U.S. Pat. No. 4,374,829), lisinopril
(U.S. Pat. No. 4,374,829), quinapril (U.S. Pat. No. 4,344,949),
ramipril (U.S. Pat. No. 4,587,258), and perindopril (U.S. Pat. No.
4,508,729), carboxyalkyl dipeptide mimics such as cilazapril (U.S.
Pat. No. 4,512,924) and benazapril (U.S. Pat. No. 4,410,520),
phosphinylalkanoyl prolines such as fosinopril (U.S. Pat. No.
4,337,201) and trandolopril. Other non-limiting examples of ACE
inhibitors include, but are not limited to, alacepril, benazepril,
captopril, ceronapril, cilazapril, delapril, enalapril,
enalaprilat, fosinopril, imidapril, lisinopril, perindopril,
quinapril, ramipril, ramiprilat, spirapril, temocapril,
trandolapril.
Adrenergic Blockers
[0049] Non-limiting examples of adrenergic blockers, both .alpha.-
and .beta.-adrenergic blockers, that may be used in the
compositions of the present invention include Beta-adrenergic
receptor blockers include, but are not limited to, atenolol,
acebutolol, alprenolol, befunolol, betaxolol, bunitrolol,
carteolol, celiprolol, hydroxalol, indenolol, labetalol,
levobunolol, mepindolol, methypranol, metindol, metoprolol,
metrizoranolol, oxprenolol, pindolol, propranolol, practolol,
sotalolnadolol, tiprenolol, tomalolol, timolol, bupranolol,
penbutolol, trimepranol, yohimbine,
2-(3-(1,1-dimethylethyl)-amino-2-hydroxypropoxy)-3-pyridenecarbonitrilHCl-
, 1-butylamino-3-(2,5-dichlorophenoxy)-2-propanol,
1-isopropylamino-3-(4-(2-cyclopropylmethoxyethyl)phenoxy)-2-propanol,
3-isopropylamino-1-(7-methylindan-4-yloxy)-2-butanol,
2-(3-t-butylamino-2-hydroxy-propylthio)-4-(5-carbamoyl-2-thienyl)thiazol,
7-(2-hydroxy-3-t-butylaminpropoxy)phthalide. The above-identified
compounds can be used as isomeric mixtures, or in their respective
levorotating or dextrorotating form.
Adrenergic Agonists
[0050] Non-limiting examples of adrenergic agonists, both .alpha.-
and .beta.-adrenergic agonists, that may be used in the
compositions of the present invention include adrafinil,
adrenalone, albuterol, amidephrine, apraclonidine, bitolterol,
budralazine, carbuterol, clenbuterol, clonidine, clorprenaline,
clonidine, cyclopentamine, denopamine, detomidine, dimetofrine,
dioxethedrine, dipivefrin, dopexamine, ephedrine, epinephrine,
etafedrine, ethylnorepinephrine, fenoterol, fenoxazoline,
formoterol, guanabenz, guanfacine, hexoprenaline,
hydroxyamphetamine, ibopamine, indanazoline, isoetharine,
isometheptene, isoproterenol, mabuterol, mephentermine,
metaproterenol, metaraminol, metazoline, methoxamine,
methylhexaneamine, methoxyphenamine, midodrine, modafinil,
moxonidine, naphazoline, norepinephrine norfenefrine, octodrine,
octopamine, oxyfedrine, oxymetazoline, phenylephrine hydrochloride,
phenylpropanolamine hydrochloride, phenylpropylmethylamine,
pholedrine, pirbuterol prenalterol, procaterol, propylhexedrine,
protokylol, pseudoephedrine, reproterol, rilmenidine, rimiterol,
ritodrine, salmeterol, solterenol, synephrine, talipexole,
terbutaline, tetrahydrozoline, tiamenidine, tramazoline,
tretoquinol, tuaminoheptane, tulobuterol, tymazoline, tyramine,
xamoterol, xylometazoline, and mixtures thereof.
Agents for Pheochromocytoma
[0051] Include but are not limited to chemotherapeutics.
Antiangina Agents
[0052] Include but are not limited to amlodipine besylate,
amlodipine maleate, betaxolol hydrochloride, bevantolol
hydrochloride, butoprozine hydrochloride, carvedilol, cinepazet
maleate, metoprolol succinate, molsidomine, monatepil maleate,
nitrates (including but not limited to glyceryl trinitrate (GTN,
nitroglycerin, Nitro-Bid), isosorbide-5-mononitrate (5-ISMN, Ismo),
amyl nitrate and nicorandil (Icorel)), primidolol, ranolazine
hydrochloride, tosifen, verapamil hydrochloride).
Antiarrhythmics
[0053] Non-limiting examples of antiarrhythmics that may be used in
the compositions of the present invention include acebutolol,
acecainide, adenosine, ajmaline, alprenolol, amiodarone, amoproxan,
aprindine, aprotinolol, atenolol, azimilide, bevantolol,
bidisomide, bretylium tosylate, bucumolol, butetolol, bunaftine,
bunitrolol, bupranolol, butidrine hydrochloride, butobendine,
capobenic acid, carazolol, carteolol, cifenline, cloranolol,
disopyramide, dofetilide, encainide, esmolol, flecainide,
hydroquinidine, ibutilide, indecainide, indenolol, ipratropium
bromide, lidocaine, lorajmine, lorcainide, meobentine, mexiletine,
moricizine, nadoxolol, nifenaolol, oxprenolol, penbutolol,
pentisomide, pilsicainide, pindolol, pirmenol, practolol,
prajmaline, procainamide hydrochloride, pronethalol, propafenone,
propranolol, pyrinoline, quinidine, sematilide, sotalol, talinolol,
tilisolol, timolol, tocainide, verapamil, viquidil, xibenolol, and
mixtures thereof.
Antiplatelet Agents
[0054] Non-limiting examples of antiplatelet agents that may be
used in the compositions of the present invention include
clopidogrel, dipyridamole, abcixamab, and ticlodipine.
Anticoagulants
[0055] Anti-coagulant agents are agents which inhibit the
coagulation pathway by impacting negatively upon the production,
deposition, cleavage and/or activation of factors essential in the
formation of a blood clot. Non-limiting examples of anticoagulants
(i.e, coagulation-related therapy) that may be used in the
compositions of the present invention include Aggrenox, Agrylin,
Amicar, Anturane, Arixtra, Coumadin, Fragmin, Heparin Sodium,
Lovenox, Mephyton, Miradon, Persantine, Plavix, Pletal, Ticlid,
Trental, Warfarin. Other "anti-coagulant" and/or "fibrinolytic"
agents include Plasminogen (to plasmin via interactions of
prekallikrein, kininogens, Factors XII, XIIIa, plasminogen
proactivator, and tissue plasminogen activator[TPA]) Streptokinase;
Urokinase: Anisoylated Plasminogen-Streptokinase Activator Complex;
Pro-Urokinase; (Pro-UK); rTPA (alteplase or activase; r denotes
recombinant); rPro-UK; Abbokinase; Eminase; Sreptase Anagrelide
Hydrochloride; Bivalirudin; Dalteparin Sodium; Danaparoid Sodium;
Dazoxiben Hydrochloride; Efegatran Sulfate; Enoxaparin Sodium;
Ifetroban; Ifetroban Sodium; Tinzaparin Sodium; retaplase;
Trifenagrel; Warfarin; Dextrans.
[0056] Still other anti-coagulant agents include, but are not
limited to, Ancrod; Anticoagulant Citrate Dextrose Solution;
Anticoagulant Citrate Phosphate Dextrose Adenine Solution;
Anticoagulant Citrate Phosphate Dextrose Solution; Anticoagulant
Heparin Solution; Anticoagulant Sodium Citrate Solution; Ardeparin
Sodium; Bivalirudin; Bromindione; Dalteparin Sodium; Desirudin;
Dicumarol; Heparin Calcium; Heparin Sodium; Lyapolate Sodium;
Nafamostat Mesylate; Phenprocoumon; Tinzaparin Sodium.
[0057] Inhibitors of platelet function are agents that impair the
ability of mature platelets to perform their normal physiological
roles (i.e., their normal function). Platelets are normally
involved in a number of physiological processes such as adhesion,
for example, to cellular and non-cellular entities, aggregation,
for example, for the purpose of forming a blood clot, and release
of factors such as growth factors (e.g., platelet-derived growth
factor (PDGF)) and platelet granular components. One subcategory of
platelet function inhibitors are inhibitors of platelet aggregation
which are compounds which reduce or halt the ability of platelets
to associate physically with themselves or with other cellular and
non-cellular components, thereby precluding the ability of a
platelet to form a thrombus.
[0058] Examples of useful inhibitors of platelet function include
but are not limited to acadesine, anagrelide (if given at doses
exceeding 10 mg/day), anipamil, argatroban, aspirin, clopidogrel,
cyclooxygenase inhibitors such as nonsteroidal anti-inflammatory
drugs and the synthetic compound FR-122047, danaparoid sodium,
dazoxiben hydrochloride, diadenosine 5',5'''-P1,P4-tetraphosphate
(Ap4A) analogs, difibrotide, dilazep dihydrochloride, 1,2- and
1,3-glyceryl dinitrate, dipyridamole, dopamine and
3-methoxytyramine, efegatran sulfate, enoxaparin sodium, glucagon,
glycoprotein IIb/IIIa antagonists such as Ro-43-8857 and L-700,462,
ifetroban, ifetroban sodium, iloprost, isocarbacyclin methyl ester,
isosorbide-5-mononitrate, itazigrel, ketanserin and BM-13.177,
lamifiban, lifarizine, molsidomine, nifedipine, oxagrelate, PGE,
platelet activating factor antagonists such as lexipafant,
prostacyclin (PGI.sub.2), pyrazines, pyridinol carbamate, ReoPro
(i.e., abciximab), sulfinpyrazone, synthetic compounds BN-50727,
BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, KC-404,
KF-4939, OP-41483, TRK-100, TA-3090, TFC-612 and ZK-36374,
2,4,5,7-tetrathiaoctane, 2,4,5,7-tetrathiaoctane 2,2-dioxide,
2,4,5-trithiahexane, theophyllin pentoxifyllin, thromboxane and
thromboxane synthetase inhibitors such as picotamide and
sulotroban, ticlopidine, tirofiban, trapidil and ticlopidine,
trifenagrel, trilinolein, 3-substituted
5,6-bis(4-methoxyphenyl)-1,2,4-triazines, and antibodies to
glycoprotein IIb/IIIa as well as those disclosed in U.S. Pat. No.
5,440,020, and anti-serotonin drugs, Clopridogrel; Sulfinpyrazone;
Aspirin; Dipyridamole; Clofibrate; Pyridinol Carbamate; PGE;
Glucagon; Antiserotonin drugs; Caffeine; Theophyllin Pentoxifyllin;
Ticlopidine.
Antihypertensives
[0059] Non-limiting examples of antihypertensives that may be used
in the compositions of the present invention include amlodipine,
benidipine, benezepril, candesartan, captopril, darodipine,
dilitazem HCl, diazoxide, doxazosin HCl, enalapril, eposartan,
losartan mesylate, felodipine, fenoldopam, fosenopril, guanabenz
acetate, irbesartan, isradipine, lisinopril, mecamylamine,
minoxidil, nicardipine HCl, nifedipine, nimodipine, nisoldipine,
phenoxybenzamine HCl, prazosin HCl, quinapril, reserpine, terazosin
HCl, telmisartan, and valsartan.
Antilipemic Agents
[0060] Non-limiting examples of antilipemic agents that may be used
in the compositions of the present invention include acipimox,
aluminum nicotinate, atorvastatin, cholestyramine resin,
colestipol, polidexide, beclobrate bezafibrate, ciprofibrate,
clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate,
fluvastatin, gemfibrozil, lovastatin, lysosomal acid lipase,
icofibrate, niacin, pirifibrate, pravastatin sodium, ronifibrate,
simfibrate, theofibrate, simvastatin, niceritrol, nicoclonate,
nicomol. oxiniacic acid, etiroxate, thyopropic acid, thyroxine,
acifran, azacosterol, benfluorex, beta-benzalbutyramide, carnitine,
chondroitin sulfate clomestrone, detaxtran, dextran sulfate sodium,
5, 8, 11, 14, 17-eicosapentaenoic acid, eritadenine, furazabol,
meglutol, melinamide, mytatrienediol, ornithine, gamma-oryzanol,
pantethine, pentaerythritol tetraacetate, alpha-phenylbutyramide,
pirozadil, probucol, beta-sitosterol, sultosilic acid (piperazine
salt), tiadenol, triparanol, xenbucin, and mixtures thereof.
Antidiabetics
[0061] Non-limiting examples of antidiabetics that may be used in
the compositions of the present invention include biguanides such
as buformin, metformin, and phenformin; hormones such as insulin;
sulfonylurea derivatives such as acetohexamide,
1-butyl-3-metanilylurea, carbutamide, chlorpropamide, glibornuride,
gliclazide, glimepiride, glipizide, gliquidone, glisoxepid,
glyburide, glybuthiazole, glybuzole, glyhexamide, glymidine,
glypinamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide;
HDL agonists; PPAR.gamma. agonists such as thiazolidinediones such
as pioglitazone, rosiglitazone, and troglitazone; and others
including acarbose, calcium mesoxalate, miglitol, and
repaglinide.
Antiinflammatory Agents
[0062] Non-limiting examples of antiinflammatory agents that may be
used in the compositions of the present invention include
Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha
Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose
Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone;
Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine
Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen;
Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate;
Clobetasone Butyrate; Clopirac; Cloticasone Propionate;
Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide;
Desoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium;
Diclofenac Sodium; Diflorasone Diacetate; Diflumidone Sodium;
Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide;
Drocinonide; Endrysone; Enlimomab; Enolicam Sodium; Epirizole;
Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac;
Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort;
Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin
Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone;
Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen;
Furobufen; Halcinonide; Halobetasol Propionate; Halopredone
Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen
Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen;
Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam;
Ketoprofen; Lofemizole Hydrochloride; Lomoxicam; Loteprednol
Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone
Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone;
Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Naproxen;
Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein;
Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride;
Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate;
Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine;
Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone;
Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex;
Salnacedin; Salsalate; Salycilates; Sanguinarium Chloride;
Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin;
Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium;
Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol
Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate;
Zidometacin; Glucocorticoids; Zomepirac Sodium. One preferred
antiinflammatory agent is aspirin.
Calcium Channel Blockers
[0063] Calcium channel blockers are a chemically diverse class of
compounds having important therapeutic value in the control of a
variety of diseases including several cardiovascular disorders,
such as hypertension, angina, and cardiac arrhythmias
(Fleckenstein, Cir. Res. v. 52, (suppl. 1), p. 13-16 (1983);
Fleckenstein, Experimental Facts and Therapeutic Prospects, John
Wiley, New York (1983); McCall, D., Curr Pract Cardiol, v. 10, p.
1-11 (1985)). Calcium channel blockers are a heterogeneous group of
drugs that prevent or slow the entry of calcium into cells by
regulating cellular calcium channels. (Remington, The Science and
Practice of Pharmacy, Nineteenth Edition, Mack Publishing Company,
Eaton, Pa., p. 963 (1995)). Most of the currently available calcium
channel blockers, and useful according to the present invention,
belong to one of three major chemical groups of drugs, the
dihydropyridines, such as nifedipine, the phenyl alkyl amines, such
as verapamil, and the benzothiazepines, such as diltiazem.
Non-limiting examples of calcium channel blockers that may be used
in the compositions of the present invention include bepridil,
clentiazem, diltiazem, fendiline, gallopamil, mibefradil,
prenylamine, semotiadil, terodiline, verapamil, amlodipine,
aranidipine, barnidipine, benidipine, cilnidipine, efonidipine,
elgodipine, felodipine, isradipine, lacidipine, lercanidpine,
manidipine, nicardipine, nifedipine, nilvadipine, nimodipine,
nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine,
lomerizine, bencyclane, etafenone, fantofarone, perhexyline, and
mixtures thereof.
CETP Inhibitors
[0064] A non-limiting example of a CETP inhibitor that may be used
in the compositions of the present invention includes
torcetrapib.
COX-2 Inhibitors
[0065] Non-limiting examples of COX-2 inhibitors that may be used
in the compositions of the present invention include compounds
according to the following: all of the compounds and substances
beginning on page 8 of Winokur WO99/20110 as members of three
distinct structural classes of selective COX-2 inhibitor compounds,
and the compounds and substances which are selective COX-2
inhibitors in Nichtberger, U.S. Pat. No. 6,136,804, Oct. 24, 2000,
entitled "Combination therapy for treating, preventing, or reducing
the risks associated with acute coronary ischemic syndrome and
related conditions", and the compounds and substances which are
selective COX-2 inhibitors in Isakson et al, PCT application
WO/09641645 published Dec. 27, 1996, filed as PCT/US 9509905 on
Jun. 12, 1995, entitled "Combination of a Cyclooxygenase-2
Inhibitor and a Leukotriene B4 Receptor Antagonist for the
Treatment of Inflammations." The meaning of COX-2 inhibitor in this
invention shall include the compounds and substances referenced and
incorporated into Winokur WO99/20110 by reference to art therein,
the compounds and substances referenced and incorporated into
Nichtberger, U.S. Pat. No. 6,136,804, Oct. 24, 2000, by reference
to art therein, and the compounds and substances which are COX-2
inhibitors referenced and incorporated into Isakson et al, PCT
application WO/09641645 published Dec. 27, 1996, filed as PCT/US
9509905 on Jun. 12, 1995, entitled "Combination of a
Cyclooxygenase-2 Inhibitor and a Leukotriene B4 Receptor Antagonist
for the Treatment of Inflammations." The meaning of COX-2 inhibitor
in this invention also includes rofecoxib, and celecoxib, marketed
as VIOXX and CELEBREX by Merck and Searle/Pfizer respectively.
Rofecoxib is discussed in Winokur, WO99/20110 as compound 3, on p.
9. Celecoxib is discussed as SC-58635 in the same reference, and in
T. Penning, Synthesis and biological evaluation of the
1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors:
identification of
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrozol-1-yl]benzenesulfonam-
ide (SC-58635, celecoxib)", J. Med. Chem. Apr. 25, 1997: 40(9):
1347-56. The meaning of COX-2 inhibitor in this invention also
includes SC299 referred to as a fluorescent diaryloxazole. C. Lanzo
et al, "Fluorescence quenching analysis of the association and
dissociation of a diarylheterocycle to cyclooxygenasel-1 and
cyclooxygenase-2: dynamic basis of cycloxygenase-2 selectivity",
Biochemistry May 23, 2000, vol. 39(20):6228-34, and in J. Talley et
al, "4,5-Diaryloxazole inhibitors of cyclooxygenase-2 (COX-2)",
Med. Res. Rev. May 1999; 19(3): 199-208. The meaning of COX-2
inhibitor in this invention also includes valdecoxib, See,
"4-[5-Methyl-3-phenylisoxazol-1-yl]benzenesulfonamide, Valdecoxib:
A Potent and Selective Inhibitor of COX-2", J. Med. Chem. 2000,
Vol. 43: 775-777, and parecoxib, sodium salt or parecoxib sodium,
See,
N-[[(5-methyl-3-phenylixoxazol-4yl)-phenyl]sulfonyl]propanimide,
Sodium Salt, Parecoxib Sodium: A Potent and Selective Inhibitor of
COX-2 for Parenteral Administration", J. Med. Chem. 2000, Vol. 43:
1661-1663. The meaning of COX-2 inhibitor in this invention also
includes the substitution of the sulfonamide moiety as a suitable
replacement for the methylsulfonyl moiety. See, J. Carter et al,
Synthesis and activity of sulfonamide-substituted 4,5-diaryl
thiazoles as selective cyclooxygenase-2 inhibitors." Bioorg. Med.
Chem. Lett Apr. 19, 1999: Vol. 9(8): 1171-74, and compounds
referenced in the article "Design and synthesis of
sulfonyl-substituted 4,5-diarylthiazoles as selective
cyclooxygenase-2 inhibitors", Bioorg. Med. Chem. Lett Apr. 19,
1999: Vol. 9(8): 1167-70. The meaning of this invention includes a
COX-2 inhibitor, NS398 referenced in two articles: Attiga et al,
"Inhibitors of Prostaglandin Synthesis Inhibit Human Prostate Tumor
Cell Invasiveness and Reduce the Release of Matrix
Metalloproteinases", 60 Cancer Research 4629-4637, Aug. 15, 2000,
and in "The cyclooxygenase-2 inhibitor celecoxib induces apoptosis
by blocking Akt activation in human prostate cancer cells
independently of Bcl-2," Hsu et al, 275(15) J. Biol. Chem.
11397-11403 (2000). The meaning of COX-2 inhibitor in this
invention includes the cyclo-oxygenase-2 selective compounds
referenced in Mitchell et al, "Cyclo-oxygenase-2: pharmacology,
physiology, biochemistry and relevance to NSAID therapy", Brit. J.
of Pharmacology (1999) vol. 128: 1121-1132, see especially p. 1126.
The meaning of COX-2 inhibitor in this invention includes so-called
NO-NSAIDs or nitric oxide-releasing-NSAIDs referred to in L.
Jackson et al, "COX-2 Selective Nonsteroidal Anti-Inflammatory
Drugs: Do They Really Offer Any Advantages?", Drugs, June, 2000
vol. 59(6): 1207-1216 and the articles at footnotes 27, and 28.
Also included in the meaning of COX-2 inhibitor in this invention
includes any substance that selectively inhibits the COX-2
isoenzyme over the COX-1 isoenzyme in a ratio of greater than 10 to
1 and preferably in ratio of at least 40 to 1 as referenced in
Winokur WO 99/20110, and has one substituent having both atoms with
free electrons under traditional
valence-shell-electron-pair-repulsion theory located on a cyclic
ring (as in the sulfylamine portion of celecoxib), and a second
substituent located on a different ring sufficiently far from said
first substituent to have no significant electron interaction with
the first substituent. The second substituent should have an
electronegativity within such substituent greater than 0.5, or the
second substituent should be an atom located on the periphery of
the compound selected from the group of a halogen F, Cl, Br or I,
or a group VI element, S or O. Thus for purposes of this last
included meaning of a COX-2 inhibitor, one portion of the COX-2
inhibitor should be hydrophilic and the other portion lipophilic.
Also included as a COX-2 inhibitor are compounds listed at page 553
in Pharmacotherapy: A Pathophysiologic Approach, Depiro et al
(McGraw Hill 1999) including nabumetone and etodolac. Recognizing
that there is overlap among the selective COX-2 inhibitors set out
in this paragraph, the intent of the term COX-2 inhibitor is to
comprehensively include all selective COX-2 inhibitors, selective
in the sense of inhibiting COX-2 over COX-1. The inventors add to
the class of COX-2 inhibitors useful in the invention the drug
bearing the name etoricoxib referenced in the Wall Street Journal,
Dec. 13, 2000, manufactured by Merck. See, also, Chauret et al.,
"In vitro metabolism considerations, including activity testing of
metabolites, in the discovery and selection of the COX-2 inhibitor
etoricoxib (MK-0663)," Bioorg. Med. Chem. Lett. 11(8): 1059-62
(Apr. 23, 2001). Another selective COX-2 inhibitor is DFU
[5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)
phenyl-2(5H)-furanone] referenced in Yergey et al, Drug Metab.
Dispos. 29(5):638-44 (May 2001). The inventors also include as a
selective COX-2 inhibitor the flavonoid antioxidant silymarin, and
an active ingredient in silymarin, silybinin, which demonstrated
significant COX-2 inhibition relative to COX-1 inhibition. The
silymarin also showed protection against depletion of glutathione
peroxidase. Zhao et al, "Significant Inhibition by the Flavonoid
Antioxidant Silymarin against 12-O-tetracecanoylphorbol
13-acetate-caused modulation of antioxidant and inflammatory
enzymes, and cyclooxygenase 2 and interleukin-1 alpha expression in
SENCAR mouse epidermis: implications in the prevention of stage I
tumor promotion," Mol. Carcinog. December 1999, Vol 26(4):321-33
PMID 10569809. Silymarin has been used to treat liver diseases in
Europe.
[0066] A number of the above-identified COX-2 inhibitors are
prodrugs of selective COX-2 inhibitors, and exert their action by
conversion in vivo to the active and selective COX-2 inhibitors.
The active and selective COX-2 inhibitors formed from the
above-identified COX-2 inhibitor prodrugs are described in detail
in WO 95/00501, published Jan. 5, 1995, WO 95/18799, published Jul.
13, 1995 and U.S. Pat. No. 5,474,995, issued Dec. 12, 1995. Given
the teachings of U.S. Pat. No. 5,543,297, entitled: "Human
cyclooxygenase-2 cDNA and assays for evaluating cyclooxygenase-2
activity," a person of ordinary skill in the art would be able to
determine whether an agent is a selective COX-2 inhibitor or a
precursor of a COX-2 inhibitor, and therefore part of the present
invention.
"Direct Thrombin Inhibitors"
[0067] Non limiting examples of direct thrombin inhibitors include
hirudin, hirugen, hirulog, agatroban, PPACK, and thrombin
aptamers.
Diuretics
[0068] Non-limiting examples of diuretics that may be used in the
compositions of the present invention include althiazide,
bendroflumethiazide, benzthiazide, buthiazide, chlorthalidone,
cyclopenthiazide, cyclothiazide, epithiazide, ethiazide,
fenquizone, indapamide, hydroflumethiazide, methyclothiazide,
meticrane, metolazone, paraflutizide, polythiazide, quinethazone,
teclothiazide, trichloromethiazide, chlormerodrin, meralluride,
mercamphamide, mercaptomerin sodium, mercumatilin sodium, mercurous
chloride, mersalyl, acefylline, 7-morpholinomethyl-theophylline,
pamabrom, protheobromine, theobromine, canrenone, oleandrin,
spironolactone, acetazolamide, ambuside, azosemide, bumetanide,
butazolamide, clopamide, clrexolone, disufamide, ethoxzolamide,
furosemide, mefruside, methazolamide, piretanide, torsemide,
tripamide, xipamide, aminometradine, amisometradine, amanozine,
amiloride, arbutin, chlorazanil, ethacrynic acid, etozolin,
hydracarbazine, isosorbide, mannitol, metochalcone, muzolimine,
perhexyline, ticrynafen, triamterene, urea, and mixtures
thereof.
Endothelin Receptor Antagonists
[0069] A non-limiting example of an endothelin receptor antagonist
that may be used in the compositions of the present invention is
bosentan.
HMG-CoA Reductase Inhibitor (Statins)
[0070] HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase is
the microsomal enzyme that catalyzes the rate limiting reaction in
cholesterol biosynthesis (HMG-CoA6Mevalonate). An HMG-CoA reductase
inhibitor inhibits HMG-CoA reductase, and as a result inhibits the
synthesis of cholesterol. A number of HMG-CoA reductase inhibitors
has been used to treat individuals with hypercholesterolemia. More
recently, HMG-CoA reductase inhibitors have been shown to be
beneficial in the treatment of stroke (Endres M, et al., Proc Natl
Acad Sci USA, 1998, 95:8880-5).
[0071] HMG-CoA reductase inhibitors useful for co-administration
with the agents of the invention include, but are not limited to,
simvastatin (U.S. Pat. No. 4,444,784), lovastatin (U.S. Pat. No.
4,231,938), pravastatin sodium (U.S. Pat. No. 4,346,227),
fluvastatin (U.S. Pat. No. 4,739,073), atorvastatin (U.S. Pat. No.
5,273,995), cerivastatin, and numerous others described in U.S.
Pat. Nos. 5,622,985; 5,135,935; 5,356,896; 4,920,109; 5,286,895;
5,262,435; 5,260,332; 5,317,031; 5,283,256; 5,256,689; 5,182,298;
5,369,125; 5,302,604; 5,166,171; 5,202,327; 5,276,021; 5,196,440;
5,091,386; 5,091,378; 4,904,646; 5,385,932; 5,250,435; 5,132,312;
5,130,306; 5,116,870; 5,112,857; 5,102,911; 5,098,931; 5,081,136;
5,025,000; 5,021,453; 5,017,716; 5,001,144; 5,001,128; 4,997,837;
4,996,234; 4,994,494; 4,992,429; 4,970,231; 4,968,693; 4,963,538;
4,957,940; 4,950,675; 4,946,864; 4,946,860; 4,940,800; 4,940,727;
4,939,143; 4,929,620; 4,923,861; 4,906,657; 4,906,624 and
4,897,402, the disclosures of which patents are incorporated herein
by reference.
[0072] Other non-limiting examples of HMG-CoA reductase inhibitors
that may be used in the compositions of the present invention
include mevastatin, pitavastatin, rosuvastatin, gemcabene, and
probucol.
Inotropic Agents
[0073] Non-limiting examples of inotropic agents that may be used
in the compositions of the present invention include acefylline,
acetyldigitoxins, 2-amino-4-picoline, amrinone, benfurodil
hemisuccinate, bucladesine, camphotamide, convallatoxin, cymarin,
denopamine, deslanoside, digitalin, digitalis, digitoxin, digoxin,
dobutamine, docarpamine, dopamine, dopexamine, enoximone,
erythrophleine, fenalsomine, gitalin, gitoxin, glycocyamine,
heptaminol, hydrastinine, ibopamine, lanatosides, loprinine,
milrinone, nerifolin, oleandrin, ouabain, oxyfedrine, pimobendan,
prenalterol, proscillaridin, resibufogenin, scillaren, scillarenin,
strophanthin, sulmazole, theobromine, vesnarinone, xamoterol, and
mixtures thereof.
"Renin Inhibitors"
[0074] Renin inhibitors are compounds which interfere with the
activity of renin. Renin inhibitors include amino acids and
derivatives thereof, peptides and derivatives thereof, and
antibodies to renin. Examples of renin inhibitors that are the
subject of United States patents are as follows: urea derivatives
of peptides (U.S. Pat. No. 5,116,835); amino acids connected by
nonpeptide bonds (U.S. Pat. No. 5,114,937); di- and tri-peptide
derivatives (U.S. Pat. No. 5,106,835); amino acids and derivatives
thereof (U.S. Pat. Nos. 5,104,869 and 5,095,119); diol sulfonamides
and sulfinyls (U.S. Pat. No. 5,098,924); modified peptides (U.S.
Pat. No. 5,095,006); peptidyl beta-aminoacyl aminodiol carbamates
(U.S. Pat. No. 5,089,471); pyrolimidazolones (U.S. Pat. No.
5,075,451); fluorine and chlorine statine or statone containing
peptides (U.S. Pat. No. 5,066,643); peptidyl amino diols (U.S. Pat.
Nos. 5,063,208 and 4,845,079); N-morpholino derivatives (U.S. Pat.
No. 5,055,466); pepstatin derivatives (U.S. Pat. No. 4,980,283);
N-heterocyclic alcohols (U.S. Pat. No. 4,885,292); monoclonal
antibodies to renin (U.S. Pat. No. 4,780,401); and a variety of
other peptides and analogs thereof (U.S. Pat. Nos. 5,071,837,
5,064,965, 5,063,207, 5,036,054, 5,036,053, 5,034,512, and
4,894,437).
Vasodilators
[0075] Non-limiting examples of vasodilators that may be used in
the compositions of the present invention include bencyclane,
cinnarizine, citicoline, cyclandelate, ciclonicate,
diisopropylamine dichloroacetate, eburnamonine, fasudil, fenoxedil,
flunarizine, ibudilast, ifenprodil, isosorbide dinitrate,
lomerixine, nafronyl, nicametate, nicergoline, nimodipine,
papaverine, pentifylline, tinofedrine, vancamine, vinpocetine,
viquidil, amotriphene, bendazol, benfurodil hemisuccinate,
benziodarone, chloracizine, chromonar, clobenfurol, clonitrate,
cloricromen, dilazep, dipyridamole, droprenilamine, efloxate,
erythrityl tetranitrate, etafenone, fendiline, floredil,
ganglefence, heart muscle extract, hexestrol
bis(.beta.-diethylaminoethyl ether), hexobendine, hydralazine,
itramin tosylate khellin, lidoflazine, mannitol hexanitrate,
medibazine, nitroglycerin, isosorbide mononitrate, isosorbide
dinitrate, and other nitrates, pentaerythritol tetranitrate,
pentrinitrol, perhexyline, pimefylline, prenylamine, propatyl
nitrate, pyridofylline, trapidil, tricromyl, trimetazidine,
trolnitrate phosphate, visnadine, aluminum nicotinate, bamethan,
bencyclane, betahistine, bradykinin, brovincamine, bufeniode,
buflomedil, butalamine, cetiedil, ciclonicate, cinepazide,
cinnarizine, cyclandelate, diisopropylamine dichloroacetate,
eledoisin, fenoxedil, flunazine, hepronicate, ifenprodil, iloprost,
inositol niacinate, isoxsuprine, kallidin, kallikrein, moxisylyte,
nafronyl, nicametate nicergoline, nicofuranose, nicotinyl alcohol,
nylidrin, pentifylline, pentoxifylline, piribedil, prostaglandin
E.sub.1, suloctidil, tolazoline, xanthinol niacinate, and mixtures
thereof.
Vasopressors
[0076] Non-limiting examples of vasopressors that may be used in
the compositions of the present invention include amezinium methyl
sulfate, angiotensin amide, dimetofrine, dopamine, etifelmin,
etilefrin, gepefrine, metaraminol, methoxamine, midodrine,
norepinephrine, pholedrine, synephrine, and mixtures thereof.
Age Crosslink Breakers (Advanced Glycosylation End-Product
Crosslink Breakers)
[0077] Non-limiting examples of AGE crosslink breakers that may be
used in the compositions of the present invention include
Alagebrium.
Age Formation Inhibitors (Advanced Glycosylation End-Product
Formation Inhibitors)
[0078] Non-limiting examples of AGE formation inhibitors that may
be used in the compositions of the present invention include
Pimagedine.
Other Actives:
[0079] Non-limiting examples of other active ingredients that may
be combined with these nebivolol compositions include, but are not
limited to, the following representative classes of compounds, as
well as their pharmaceutically acceptable salts, isomers, esters,
ethers and other derivatives:
[0080] analgesics and anti-inflammatory agents, such as aloxiprin,
auranofin, azapropazone, benorylate, capsaicin, celecoxib,
diclofenac, diflunisal, etodolac, fenbufen, fenoprofen calcium,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
leflunomide, meclofenaminc acid, mefenamic acid, nabumetone,
naproxen, oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam,
rofecoxib, sulindac, tetrahydrocannabinol, tramadol and
tromethamine;
[0081] antihelminthics, such as albendazole, bephenium
hydroxynaphthoate, cambendazole, dichlorophen, ivermectin,
mebendazole, oxamniquine, oxfendazole, oxantel embonate,
praziquantel, pyrantel embonate and thiabendazole;
[0082] anti-asthma agents, such as zileuton, zafirlukast,
terbutaline sulfate, montelukast, and albuterol;
[0083] anti-bacterial agents, such as alatrofloxacin, azithromycin,
baclofen, benzathine penicillin, cinoxacin, ciprofloxacin HCl,
clarithromycin, clofazimine, cloxacillin, demeclocycline,
dirithromycin, doxycycline,
[0084] erythromycin, ethionamide, furazolidone, grepafloxacin,
imipenem, levofloxacin, lorefloxacin, moxifloxacin HCl, nalidixic
acid, nitrofurantoin, norfloxacin, ofloxacin, rifampicin,
rifabutine, rifapentine, sparfloxacin,
[0085] spiramycin, sulphabenzamide, sulphadoxine,
sulphamerazine,
[0086] ulphacetamide, sulphadiazine, sulphafurazole,
sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim,
trovafloxacin, and vancomycin;
[0087] anti-viral agents, such as abacavir, amprenavir,
delavirdine, efavirenz, indinavir, lamivudine, nelfinavir,
nevirapine, ritonavir, saquinavir, and stavudine;
[0088] anti-depressants, such as amoxapine, bupropion, citalopram,
clomipramine, fluoxetine HCl, maprotiline HCl, mianserin HCl,
nortriptyline HCl, paroxetine HCl, sertraline HCl, trazodone HCl,
trimipramine maleate, and venlafaxine HCl;
[0089] anti-epileptics, such as beclamide, carbamazepine,
clonazepam, ethotoin, felbamate, fosphenytoin sodium, lamotrigine,
methoin, methsuximide, methylphenobarbitone, oxcarbazepine,
paramethadione, phenacemide,
[0090] phenobarbitone, phenyloin, phensuximide, primidone,
sulthiame, tiagabine HCl, topiramate, valproic acid, and
vigabatrin;
[0091] anti-fungal agents, such as amphotericin, butenafine HCl,
butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole,
flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole,
natamycin,
[0092] nystatin, sulconazole nitrate, oxiconazole, erbinafine HCl,
terconazole, tioconazole and undecenoic acid;
[0093] anti-gout agents, such as allopurinol, probenecid and
sulphinpyrazone;
[0094] anti-malarials, such as amodiaquine, chloroquine,
chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil
HCl, pyrimethamine and quinine sulfate;
[0095] anti-migraine agents, such as dihydroergotamine mesylate,
ergotamine tartrate, frovatriptan, methysergide maleate,
naratriptan HCl, pizotifen maleate, rizatriptan benzoate,
sumatriptan succinate, and zolmitriptan;
[0096] anti-muscarinic agents, such as atropine, benzhexol HCl,
biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide,
oxyphencyclimine HCl and tropicamide;
[0097] anti-neoplastic agents and immunosuppressants, such as
aminoglutethimide, amsacrine, azathioprine, bicalutamide,
bisantrene, busulfan, camptothecin, capecitabine, chlorambucil,
cyclosporin, dacarbazine,
[0098] ellipticine, estramustine, etoposide, irinotecan, lomustine,
melphalan, mercaptopurine, methotrexate, mitomycin, mitotane,
mitoxantrone, mofetil mycophenolate, nilutamide, paclitaxel,
procarbazine HCl, sirolimus, tacrolimus, tamoxifen citrate,
teniposide, testolactone, topotecan HCl, and toremifene
citrate;
[0099] anti-protozoal agents, such as atovaquone, benznidazole,
clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide
furoate, dinitolmide, furazolidone, metronidazole, nimorazole,
nitrofurazone, ornidazole and tinidazole;
[0100] anti-psychotics, such as aripiprazole, clozapine,
ziprasidone, haloperidol, molindone, loxapine, thioridazine,
molindone, thiothixene, pimozide, fluphenazine, risperidone
mesoridazine, quetiapine, trifluoperazine, chlorprothixene,
chlorpromazine, perphenazine, trifluopromazine, olanzapine;
[0101] anti-thyroid agents, such as carbimazole, paracalcitol, and
propylthiouracil;
[0102] anti-tussives, such as benzonatate;
[0103] anxiolytics, sedatives, hypnotics and neuroleptics, such as
alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam,
bromperidol, brotizolam, butobarbitone, carbromal,
chlordiazepoxide, chlormethiazole, chlorpromazine, chlorprothixene,
clonazepam, clobazam, clotiazepam, clozapine, diazepam, droperidol,
ethinamate, flunanisone, flunitrazepam, triflupromazine,
flupenthixol decanoate, fluphenthixol decanoate, flurazepam,
gabapentin, haloperidol, lorazepam, lormetazepam, medazepam,
meprobamate, mesoridazine, methaqualone, methylphenidate,
midazolam, molindone, nitrazepam,
[0104] olanzapine, oxazepam, pentobarbitone, perphenazine pimozide,
prochlorperazine, pseudoephedrine, quetiapine, risperidone,
sertindole, sulpiride, temazepam, thioridazine, triazolam,
zolpidem, and zopiclone;
[0105] corticosteroids, such as beclomethasone, betamethasone,
budesonide, cortisone acetate, desoxymethasone, dexamethasone,
fludrocortisone acetate, flunisolide, fluocortolone, fluticasone
propionate, hydrocortisone, methylprednisolone, prednisolone,
prednisone and triamcinolone;
[0106] anti-parkinsonian agents, such as apomorphine, bromocriptine
mesylate, lysuride maleate, pramipexole, ropinirole HCl, and
tolcapone;
[0107] gastro-intestinal agents, such as bisacodyl, cimetidine,
cisapride, diphenoxylate HCl, domperidone, famotidine,
lanosprazole, loperamide, mesalazine, nizatidine, omeprazole,
ondansetron HCL, rabeprazole sodium, ranitidine HCl and
sulphasalazine;
[0108] keratolytics, such as acetretin, calciprotriene,
calcifediol, calcitriol, cholecalciferol, ergocalciferol,
etretinate, retinoids, targretin, and tazarotene;
[0109] lipid regulating agents, such as atorvastatin, bezafibrate,
cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluvastatin,
gemfibrozil, pravastatin, probucol, and simvastatin;
[0110] muscle relaxants, such as dantrolene sodium and tizanidine
HCl;
[0111] nutritional agents, such as calcitriol, carotenes,
dihydrotachysterol, essential fatty acids, non-essential fatty
acids, phytonadiol, vitamin A, vitamin B.sub.2, vitamin D, vitamin
E and vitamin K;
[0112] opioid analgesics, such as codeine, dextropropoxyphene,
diamorphine, dihydrocodeine, fentanyl, meptazinol, methadone,
morphine, nalbuphine and pentazocine;
[0113] sex hormones, such as clomiphene citrate, cortisone acetate,
danazol, dehydroepiandrosterone, ethynyl estradiol, finasteride,
fludrocortisone, fluoxymesterone, medroxyprogesterone acetate,
megestrol acetate, mestranol, methyltestosterone, norethisterone,
norgestrel, oestradiol, conjugated estrogens,
[0114] progesterone, rimexolone, stanozolol, stilbestrol,
testosterone and tibolone;
[0115] stimulants, such as amphetamine, dexamphetamine,
dexfenfluramine, fenfluramine and mazindol;
[0116] drugs for rheumatoid arthritis such as methotrexate,
auranofin, aurothioglucose and gold sodium thiomalate;
[0117] drugs for osteoporosis such as alendronate and
raloxifene;
[0118] local anesthetics;
[0119] anti-herpes drugs such as acyclovir, valacyclovir and
famcyclovir;
[0120] anti-emetics such as ondansetron and granisetron;
Further examples of other active agents which may be suitable for
this invention include, without limitation: abecarnil,
acamprostate, acavir, acebutolol, aceclofenac, acemetacin,
acetaminophen, acetaminosalol, acetanilide, acetohexamide,
acetophenazine maleate, acetophenazine, acetoxolone,
acetoxypregnenolone, acetretin, acrisorcin, acrivastine, acyclovir,
adinazolam, adiphenine hydrochloride, adrafinil, adrenolone,
agatroban, ahnitrine, akatinol, alatrofloxacin, albendazole,
albuterol, aldioxa, alendronate, alfentanil, alibendol,
alitretinoin, allopurinol, allylamines, allylestrenol,
alminoprofen, almotriptan, alosetron, aloxiprin, alprazolam,
alprenolol, amantadine, ambucetamide, amidephrine, amidinomycin,
amiloride, aminoarylcarboxylic acid derivatives, aminoglutethimide,
aminoglycosides, aminopentamide, aminopromazine, aminorex,
amiodarone, amiphenazole, amiprilose, amisulpride, amitriptyline,
amlexanox, amlodipine, amodiaquine, amosulalol, amotriphene,
amoxapine, amoxicillin, amphecloral, amphetamine, amphomycin,
amphotericin, ampicillin, ampiroxicam, amprenavir, amrinone,
amsacrine, amyl nitrate, amylobarbitone, anagestone acetate,
anastrozole, andinocillin, androstenediol,
androstenediol-17-acetate, androstenediol-17-benzoate,
androstenediol-3-acetate, androstenediol-3-acetate-17-benzoate,
androstenedione, androsterone acetate, androsterone benzoate,
androsterone propionate, androsterone, angiotensin, anidulatungin,
aniracetam, apazone, apicycline, apoatropine, apomorphine,
apraclonidine, aprepitant, aprotinin, arbaprostil, ardeparin,
aripiprazole, amikacin, arotinolol, arstiinol, arylacetic acid
derivatives, arylalkylamines, arylbutyric acid derivatives,
arylcarboxylic acids, arylpiperazines, arylpropionic acid
derivatives, aspirin, astemizole, atenolol, atomoxetine,
atorvastatin, atovaquone, atropine, auranofn, azapropazone,
azathioprine, azelastine, azetazolamide, azithromycin, baclofen,
bambuterol, bamethan, barbitone, barnidipine, basalazide,
beclamide, beclobrate, befimolol, bemegride, benazepril,
bencyclane, bendazac, bendazol, bendroflumethiazide, benethamine
penicillin, benexate hydrochloride, benfurodil hemisuccinate,
benidipine, benorylate, bentazepam, benzhexyl, benziodarone,
benznidazole, benzoctamine, benzodiazepine derivatives,
benzodiazepine, benzonatate, benzphetamine, benzylmorphine,
beperiden, bephenium hydroxynaphthoate, bepridil, betahistine,
betamethasone, betaxolol, bevantolol, bevonium methyl sulfate,
bexarotene, bezadoxifine, bezafibrate, bialamicol, biapenem,
bicalutamide, bietamiverine, bifonazole, binedaline, binifibrate,
biricodar, bisacodyl, bisantrene, bisoprolol, bitolterol,
bopindolol, boswellic acid, bradykinin, bretylium, bromazepam,
bromocriptine, bromperidol, brotizolam, brovincamine, buciclate,
bucloxic acid, bucumolol, budralazine, buieniode, bufetolol,
buflomedil, bufuralol, bumetanide, bunitrolol, bupranolol,
buprenorphine, buproprion, buspirone, busulfan, butalamine,
butarphenol, butaverine, butenafine, butenatme, butidrine
hydrochloride, butobarbitone, butoconazole nitrate, butoconazole,
butofilol, butorphenol, butropium bromide, cabergoline,
calcifediol, calcipotriene, calcitriol, caldibine, cambendazole,
camioxirole, camostat, camposterol, camptothecin, candesartan,
candoxatril, capecitabine, caprate, capsaicin, captopril,
carazolol, carbacephems, carbamates, carbamezepine, carbapenems,
carbarsone, carbatrol, carbenoxolone, carbimazole, carbromal,
carbuterol, carisoprodol, carotenes, caroverine, carteolol,
carvedilol, cefaclor, cefazolin, cefbuperazone, cefepime,
cefoselis, ceftibuten, celcoxib, celecoxib, celiprolol, cephaeline,
cephalosporin C, cephalosporins, cephamycins, cerivastatin,
certoparin, cetamolol, cetiedil, cetirizine, cetraxate,
chloracizine, chlorambucil, chlorbetamide, chlordantoin,
chlordiazepoxide, chlormadinone acetate, chlormethiazole,
chloroquine, chlorothiazide, chlorpheniramine, chlorphenoxamide,
chlorphentermine, chlorproguanil, chlorpromazine, chlorpropamide,
chlorprothixene, chlortetracycline, chlorthalidone,
cholecalciferol, chromonar, ciclesonide, ciclonicate, cidofivir,
ciglitazone, cilansetron, cilostazol, cimetidine, cimetropium
bromide, cinepazet maleate, cinnamedrine, cinnarizine, cinolazepam,
cinoxacin, ciprofibrate, ciprofloxacin, cisapride, cisplatin,
citalopram, citicoline, clarithromycin, clebopride, clemastine,
clenbuterol, clidanac, clinofibrate, clioquinol, clobazam,
clobenfurol, clobenzorex, clofazimine, clofibrate, clofibric acid,
cloforex, clomipramine, clonazepam, clonidine, clonitrate,
clopidogrel, clopirac indomethacin, cloranolol, cloricromen,
clorprenaline, clortermine, clotiazepam,: clotrimazole,
cloxacillin, clozapine, cmepazide, codeine methyl bromide, codeine
phosphate, codeine sulfate, codeine, colloidal bismuth subcitrate,
cromafiban, cromolyn, cropropamide, crotethamide, curcumin,
cyclandelate, cyclarbamate, cyclazocine, cyclexedrine, cyclizine,
cyclobenzaprine, cyclodrine, cyclonium iodide, cyclopentamine,
cyclosporin, cypionate, cyproheptadine, cyproterone acetate,
cytarabine, dacarbazine, dalfopristine, dantrolene sodium,
dapiprazole, darodipine, decanoate, decitabine, decoquinate,
dehydroemetine, delavirdine, del aviridine, demeclo cycline,
denopamine, deramciclone, descitalopram, desipramine,
desloratadine, 3-ketodesogeskel, desomorphine, desoxymethasone,
detomidine, dexamphetamine, dexanabinol, dexchlorpheniramine,
dexfenfluramine, dexmethylphenidate, dexrazoxane, dextroamphetamine
sulfate, dextroamphetamine, dextropropoxyphene, DHEA, diacetate,
diamorphine, diazemine, diazepam, diaziquinone, diazoxide,
dibromopropamidine, dichlorophen, diclofenac, dicoumarol,
didanosine, dideoxyadenosine, diethylpropion, difemerine,
difenamizole, diflunisal, digitoxin, digoxin, dihidroergotamine,
dihydrocodeine, diLydrocodeinone enol acetate, dihydroergotamine
mesylate, dihydroergotamine, dihydrogesterone, dihydromorphine,
dihydropyridine derivatives, dihydrostreptomycin,
dihydrotachysterol, dihydroxyaluminum acetylsalicylate,
diiodohydroxyquinoline, diisopromine, dilazep, dilevalol,
dilitazem, diloxanide furoate, diloxanide, diltiazem, dimefline,
dimenhydrinate, dimethisterone, dimetotrine, dimorpholamine,
dinitolmide, dioxaphetyl butyrate, dioxethedrine, diphemethoxidine,
diphenhydramine, diphenoxylate, diphetarsone, dipivefrin, diponium
bromide, dipyridamole, dirithromycin, disopyramide, divalproex
sodium, dofetilide, domperidone, donezepil, dopexamine, dopradil,
dosmalfate, doxapram, doxazosin, doxefazepam, doxepin, doxycycline,
drofenine, dromostanolone propionate, dromostanolone, dronabinol,
droperidol, droprenilamine, d-threo-methylphenidate, duloxetine,
ebrotidine, eburnamonine, ecabet, ecenofloxacin, econazole nitrate,
edavarone, edoxudine, efavirenz, effivarenz, efloxate, eledoisin,
eletriptan, elgodipine, ellipticine, emepronium bromide, emetine,
enalapril, enanthate, encainide, enlopitat, enoximone, enprostil,
entacapone, epanolol, ephedrine, epinastine, epinephrine,
epirubicin, epleronone, eposartan, ergocalciferol, ergoloid
mesylates, ergotamine, ertapenum, erythromycin, erytlirityl
tetranitrate, esaprazole, escitalopram, esmolol, esomeprazole,
esonarimod, estazolam, estradiol benzoate, estramustine, eskiol
succinate, estrone acetate, estrone sulfate, etafedrine, etafenone,
ethacrynic acid, ethamivan, ethinamate, ethinyleskadiol 3-acetate,
ethinyleskadiol 3-benzoate, ethinylestradiol, ethionamide,
ethisterone (17a-ethinyltestosterone), ethopropazine, ethotoin,
ethoxyphenamine, ethylestrenol, ethylmorphine, ethylnorepinephrine,
ethynodiol diacetate, etodolac, etofibrate, etoposide, etoricoxib,
etretinate, everolimus, exalamide, examestane, examorelin,
ezemitibe, falecalcitriol, famciclovir, famotidine, fantofarone,
farapenum, farglitazar, fasudil, felbamate, felodipine, fenalamide,
fenbuLen, fenbutrazate, fendiline, fenfluramine, fenoldopam,
fenoprofen, fenoterol, fenoverine, fenoxazoline, fenoxedil,
fenpiprane, fenproporex, fenspiride, fentanyl, fexofenadine,
flavoxate, flecainide, flopropione, floredil, floxuridine,
fluconazole, flucytosine, fludarabine, fludiazopam,
fludrocortisone, flulenamic acid, flunanisone, flunarizine,
flunisolide, flunitrazepam, fluocortolone, fluoxetine, flupenthixol
decanoate, fluphenazine decanoate, fluphenazine enanthate,
fluphenazine, fluproquazone, flurazepam, flurbiprofen,
fluorogestone acetate, fluticasone propionate, fluvastatin,
fluvoxamine, fominoben, formoterol, foscarnet, foscarnet,
fosinopril, fosphenyloin, frovatirptan, fudosteine, fumagillin,
furazolidone, furazolidone, furfurylmethyl amphetamine, furosemide,
gabapentin, gabexate, gaboxadol, galanthamine, gallopamil,
gammaparin, gancyclovir, ganglefene, gefarnate, gemcitabine,
gemfibrozil, gepirone, gestadene, ghrelin, glatiramer, glaucarubin,
glibenclamide, gliclazide, glimepiride, glipizide, gluconic acid,
glutamicacid, glyburide, glyceryl trinitrate, glymepiride,
granisetron, grepafloxacin, griseofulvin, guaiazulene, guanabenz,
guanfacine, halofankine, haloperidol decanoate, haloperidol,
haloxazolam, hepronicate, heptanoate, hexobendine, hexoprenaline,
hydramitrazine, hydrazides, hydro chlorothi azide, hydrocodone,
hydrocortisone, hydromorphone, hydroxyamphetamine,
hydroxymethylprogesterone acetate, hydroxymethylprogesterone,
hydroxyprogesterone acetate, hydroxyprogesterone caproate,
hydroxyprogesterone, hymecromone, hyoscyamine, ibopamine,
ibudilast, ibutenac, ibuprofen, ibutilide, idoxuridine, ifenprodil,
igmesine, iloprost, imatinib, imidapril, imidazoles, imipenem,
imipramine, imolamine, incadronic acid pergolide, indanazoline,
indenolol, indinavir, indomethacin, indoramin, inosinepranobex,
inositol niacinate, iodoquinol, ipidracine, iproniazid, irbesartan,
irinotecan, irsogladine, isobutyrate, isocaprate esters,
isoetharine, isometheptene, isoproterenol, isosorbide dinitrate,
isosorbide mononitrate, isosorbide dinitrate, isoxsuprine,
isradipine, itasetron, itraconazole, itramintosylate, ivermectin,
kallidin, kallikrein, kanamycin, ketamine, ketoconazole,
ketoprofen, ketorolac, ketotifen, labetalol, lafutidine, lamifiban,
lamivudine, lamotrigine, lanatoside c, lansoprazole, lasofoxifene,
leflunomide, leminoprazole, lercanadipine, lesopitron, letrozole,
leucovorin, levalbuterol, levallorphan, levetiracetam,
levetriacetam, levobunolol, levodopa, levofloxacin,
levophacetoperane, levorphanol, lidocaine, lidoflazine, lifibrol,
limaprost, linezolid, lintitript, liranaftate, lisinopril,
lisuride, lobeline, lobucavir, lodoxamide, lomefloxacin,
lomerizine, lomustine, loperamide, lopinavir, loprazolam,
loracarbef, loratadine, lorazepam, lorefloxacin, lormetazepam,
losartan, lovasatain, lovastatin, loxapine succinate, loxapine,
1-threo methylphenidate, lumiracoxib, lysine acetylsalicylate,
lysozyme, lysuride, mabuterol, mafenide, magnesium
acetylsalicylate, malgramostin, mannitol hexanitrate, maprotiline,
mazindol, mebendazole, meclizine, meclofenamic acid,
mecloxaminepentapiperide, medazepam,: medibazine, medigoxin,
medrogestone, medroxyprogesterone acetate, mefenamic acid,
mefenorex, mefloquin, mefloquine, megestrol acetate, melengestrol
acetate, melphalan, mematine, mepenzolate bromide, meperidine,
mephenoxalone, mephentermine, mepindolol, mepixanox, meprobamate,
meptazinol, mercaptopurine, merropenum, mesalamine, mesalazine,
mesoridazine besylate, mesoridazine, metaclazepam, metamfepramone,
metampicillin, metaproterenol, metaraminol, methacycline, methadone
hydrochloride, methadone, methamphetamine, methaqualone,
methamphetamine, methoin, methotrexate, methoxamine, methsuximide,
methylhexaneamine, methylphenidate d-threo-methylphenidate,
methylphenidate, methylphenobarbitone, methylprednisolone,
methysergide, metiazinic acid, metizoline, metoclopramide,
metolazone, metoprolol, metoxalone, metripranolol, metronidazole,
mexiletine, mexilitene, metaxalone, mianserin, mibefradil,
miconazole, midazolam, midodrine, miglitol, milnacipran, milrinone,
minoxidil, mirtazapine, misoprostol, mitomycin, mitotane,
mitoxantrone, mizolastine, modafinil, mofebutazone, mofetil,
molindone hydrochloride, molindone, molsidomine, monatepil,
montelukast, monteplase, moprolol, moricizine, morphine
hydrochloride, morphine sulfate, morphine, morpholine salicylate,
mosapramine, moxifloxacin, moxisylvyte, moxonidine, mycophenolate,
nabumetone, nadolol, nadoxolol, nadroparin, nafamostat, nafronyl,
naftopidil, nalbuphine, nalidixic acid, nalmefene, nalorphine,
naloxone, naltrexone, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, nandrolone cyclohexane-propionate,
nandrolone decanoate, nandrolone furylpropionate, nandrolone
phenpropionate, naphazoline, naproxen, naratriptan, natamycin,
nateglinide, nebivalol, nedocromil, nefazodone, nefopam,
nelfinavir, nemonapride, neomycin undecylenate, neomycin, neokofin,
nesiritide, n-ethylamphetamine, nevibulol, nevirapine, nexopamil,
nicametate, nicardipine, nicergoline, nicofibrate, nicofuranose,
nicomorphine, nicorandil, nicotinyl alcohol, nicoumalone,
nifedipine, nifenalol, nikethamide, nilutamide, nilvadipine,
nimodipine, nimorazole, nipradilol, nisoldipine, nitisonone,
nitrazepam, nitrofurantoin, nitrofurazone, nitroglycerin,
nizatidine, norastemizole, norepinephrine, norethynodrel,
norfenefrine, norfloxacin, norgestimate, norgeskel, norgestrienone,
normethadone, normethisterone, normorphine, norpseudoophedrine,
nortriptyline, novantrone, nylidrin, nystatin, octamylamine,
octodrine, octopamine, ofloxacin, olanzapine, olanzapine,
olapatadine, olmesartan, olopatidine, olsalazine, omapatrilat,
omeprazole, ondasetron, opium, oprevelkin, orlistat, ornidazole,
ornoprostil, oseltamivir, oxaliplatin, oxamniquine, oxandrolone,
oxantel embonate, oxaprozin, oxatomide pemirolast, oxatomide,
oxazopam, oxcarbazepine, oxfendazole, oxiconazole, oxiracetam,
oxolinicacid, oxprenol, oxycodone, oxyfedrine, oxymetazoline,
oxymorphone, oxyphenbutazone, oxyphencyclimine, oxyprenolol,
ozagrel, paclitaxel, palonosetron, pantoprazole, papaverine,
paracalcitol, paramethadione, parecoxib, pariprazole, paromomycin,
paroxetine, parsalmide, pazinaclone, pemoline, penbutolol,
penciclovir, penicillin G benzathine, penicillin G procaine,
penicillin V, penicillins, pentaerythritol tetranitrate,:
pentaerythritol tetranitrate, pentapiperide, pentazocine,
pentifylline, pentigetide, pentobarbitone, pentorex,
pentoxifylline, pentrinitrol, perbuterol, perenzepine, pergolide,
perhexyline, perindopril erbumine, perospone, perphenazine
pimozide, perphenazine, phanquinone, phenacemide, phenacetin,
phenazopyridine, phencarbamide, phendimetrazine, phenelzine,
phenindione, phenmetrazine, phenobarbitone, phenoperidine,
phenothiazines, phenoxybenzamine, phensuximide, phentermine,
phentolamine, phenylsalicylate, phenylacetate, phenylbutazone,
phenylephrinehydrochloride, phenylpropanolamine hydrochloride,
phenylpropanolaminehydrochloride, phenylpropyl-methylamine,
phenyloin, phloroglucinol, pholedrine, physostigwine salicylate,
physostigmine, phytonadiol, phytosterols, piapenum, picilorex,
piclamilast, picrotoxin, picumast, pifarnine, pilsicainide,
pimagedine, pimeclone, pimecrolimus, pimethylline, pimozide,
pinaverium bromide, pindolol, pioglitazone, piperacillin,
piperazine estrone sulfate, piperazine derivatives, piperilate,
piracetam, pirbuterol, pirenzepine, piribedil, pirifibrate,
piroxicam, pitavastatin, pizotyline, plaunotol, polaprezinc,
polybenzarsol, polyestrol phosphate, practolol, pralnacasan,
pramipexole, pranlukast, pravastatin, prazepam, praziquantel,
prazosin, pregabalin, prenalterol, prenylamine, pridinol, prifinium
bromide, primidone, primipramine, probenecid, probucol,
procainamide, procarbazine, procaterol, prochlorperazine,
proguanil, pronethalol, propafenone, propamidine, propatyl nitrate,
propentoffyline, propionate, propiram, propoxyphene, propranolol,
propylhexedrine, propylthiouracil, protokylol, protriptyline,
proxazole, pseudoephedrine, purines, pyrantel embonate, pyrazoles,
pyrazolones, pyridofylline, pyrimethamine, pyrimidines,
pyrrolidones, quazepam, quetiapine, quetuapine, quinagolide,
quinapril, quinestrol, quinfamide, quinidine, quinine sulfate,
quinolones, quinupritin, rabalzotan, rabeprazole sodium,
rabeprazole, racefimine, ramahroban, ramipril, ranitidine,
ranolazine, ransoprazole, rasagiline, rebamipide, refludan,
repaglinide, repinotan, repirinast, reproterol, reserpine,
retinoids, ribavirin, rifabutine, rifampicin, rifapentine,
rilmenidine, riluzole, rimantadine, rimiterol, rioprostil,
risperidone, ritanovir, ritapentine, ritipenem, ritodrine,
ritonavir, rivastigmine, rizatriptan, rociverine, rofecoxib,
rohypnol, rolipram, romoxipride, ronifibrate, ropinirole,
ropivacaine, rosaprostol, rosiglitazone, rosuvastatin, rotinolol,
rotraxate, roxatidine acetate, roxindole, rubitecan, salacetamide,
salicin, salicylamide, salicylic acid derivatives, salmeterol,
saquinavir, saquinavir, scopolamine, secnidazole, selegiline,
semotiadil, sertindole, sertraline, sibutramine,
sildenafil, simBibrate, simvastatin, siramesine, sirolimus,
sitaxsentan, sofalcone, somotiadil, sorivudine, sotalol, soterenol,
sparfloxacin, spasmolytol, spectinomycin, spiramycin, spizofurone,
stavudine, streptomycin, succinylsulfathiazole, sucralfate,
sufentanil, sulconazole nitrate, sulfacetamide, sulfadiazine,
sulfaloxicacid, sulfarside, sulfmalol, sulindac, suloctidil,
sulphabenzamide, sulphacetamide, sulphadiazine, sulphadoxine,
sulphafurazole, sulphamerazine, sulphamethoxazole, sulphapyridine,
sulphasalazine, sulphinpyrazone, sulpiride, sulthiame, sultopride,
sulbroponium, sumanirole, sumahriptan, sunepihon, superoxide
dismutase, suplatast, suramin sodium, synephrine, tacrine,
tacrolimus, tacrolimus, tadalafil, talinolol, talipexole,
tamoxifen, tamsulosin, targretin, tazanolast, tazarotene,
tazobactum, tecastimezole, teclozan, tedisamil, tegaserod,
telenzepine, telmisartan, temazepam, teniposide, teprenone,
terazosin, terbenafine, terbinafine, terbutaline sulfate,
terbutaline, terconazole, terfenadine, terodiline, terofenamate,
tertatolol, testolactone, 4-dihydrotestosterone, tetracyclics,
tetracycline, tetrahydrocannabinol, tehrahydrozoline, thalidomide,
theofibrate, thiabendazole, thiazinecarboxamides, thiocarbamates,
thiocarbamizine, thiocarbarsone, thioridazine, thiothixene,
tiagabine, tiamenidine, tianeptine, tiaprofenic acid, tiaramide,
ticlopidine, tigloidine, tilisolol, timolol, tinidazole,
tinofedrine, tinzaparin, tioconazole, tipranavir, tirapazamine,
tirofiban, tiropramide, titanicene, tizanadine, tizanidine,
tizinadine, tocainide, tolazamide, tolazoline, tolbutamide,
tolcapone, tolciclate, tolfenamic acid, toliprolol, tolteridine,
tolterodine, tonaberstat, topiramate, topotecan, torasemide,
toremifene cibrate, toremifene, tosufloxacin, tramadol,
tramazoline, trandolapril, tranilast, tranylcypromine, trapidil,
traxanox, trazodone, tretoquinol, triacetin, triamcinolone,
triampterine, triamterene, triazolam, trifluoperazine
hydrochloride, trifluoperazine, triflupromazine, trihexyphenidyl,
trimazosin, trimebutine, trimetazidine, trimethoprim, trimgestone,
trimipramine, trimoprostil, trithiozine, troglitazone, trolnibrate
phosphate, tromethamine, tropicamide, trovafloxacin, troxipide,
tuaminoheptane, tulobuterol, tymazoline, tyramine, undecanoate,
undecanoic acid, urinastatin, valacyclovir, valdecoxib, valerate,
valganciclovir, valproic acid, valsartan, vancomycin, vardenafil,
venlafaxine, venorelbine, verapamil, verapimil, vidarabine,
vigabakin, vincamine, vinpocetine, viomycin, viquidil, visnadine,
vitamin a derivatives, vitamin a, vitamin b
[0121].sub.2, vitamin d, vitamin e, vitamin k, voglibose,
voriconazole, xaliproden, xamoterol, xanthinol niacinate,
xenytropium bromide, xibenolol, ximelagatran, xylometazoline,
yohimbine, zacopride, zafirlukast, zalcitabine, zaleplon,
zanamivir, zatebradine, ziconotide, zidovudine, zileuton,
zimeldine, zinc propionate, ziprasidone, zolimidine, zolmitriptan,
zolpidem, zonisamide, zopiclone, and mixtures thereof.
Formulation
[0122] The nebivolol compositions of the present invention may be
administered by various means, depending on their intended use, as
is well known in the art. For example, if compositions of the
present invention are to be administered orally, they may be
formulated as tablets, capsules, granules, powders, suspensions or
syrups. Alternatively, formulations of the present invention may be
administered parenterally as injections (intravenous, intramuscular
or subcutaneous), drop infusion preparations or suppositories. For
application by the ophthalmic mucous membrane route, compositions
of the present invention may be formulated as eyedrops or eye
ointments. These formulations may be prepared by conventional
means, and, if desired, the compositions may be mixed with any
conventional additive, such as an excipient, a binder, a
disintegrating agent, a lubricant, a corrigent, a solubilizing
agent, a suspension aid, an emulsifying agent or a coating
agent.
[0123] In formulations of the subject invention, wetting agents,
emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents,
coating agents, sweetening, flavoring and perfuming agents,
preservatives and antioxidants may be present in the formulated
agents.
[0124] Subject compositions may be suitable for oral, nasal,
topical (including buccal and sublingual), rectal, vaginal, aerosol
and/or parenteral administration. The formulations may conveniently
be presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. The amount of composition that
may be combined with a carrier material to produce a single dose
vary depending upon the subject being treated, and the particular
mode of administration.
[0125] Methods of preparing these formulations include the step of
bringing into association compositions of the present invention
with the carrier and, optionally, one or more accessory
ingredients. In general, the formulations are prepared by uniformly
and intimately bringing into association agents with liquid
carriers, or finely divided solid carriers, or both, and then, if
necessary, shaping the product. Formulations suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia), each containing a predetermined
amount of a subject composition thereof as an active ingredient.
Compositions of the present invention may also be administered as a
bolus, electuary, or paste.
[0126] In solid dosage forms for oral administration (capsules,
tablets, pills, dragees, powders, granules and the like), the
subject composition is mixed with one or more pharmaceutically
acceptable carriers, such as sodium citrate or dicalcium phosphate,
and/or any of the following: (1) fillers or extenders, such as
starches, lactose, sucrose, glucose, mannitol, and/or silicic acid;
(2) binders, such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia;
(3) humectants, such as glycerol; (4) disintegrating agents, such
as agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate; (5) solution
retarding agents, such as paraffin; (6) absorption accelerators,
such as quaternary ammonium compounds; (7) wetting agents, such as,
for example, acetyl alcohol and glycerol monostearate; (8)
absorbents, such as kaolin and bentonite clay; (9) lubricants, such
a talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl sulfate, and mixtures thereof; and (10)
coloring agents. In the case of capsules, tablets and pills, the
compositions may also comprise buffering agents. Solid compositions
of a similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or
milk sugars, as well as high molecular weight polyethylene glycols
and the like.
[0127] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the subject composition moistened with an inert liquid
diluent. Tablets, and other solid dosage forms, such as dragees,
capsules, pills and granules, may optionally be scored or prepared
with coatings and shells, such as enteric coatings and other
coatings well known in the pharmaceutical-formulating art.
[0128] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the subject
composition, the liquid dosage forms may contain inert diluents
commonly used in the art, such as, for example, water or other
solvents, solubilizing agents and emulsifiers, such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
oils (in particular, cottonseed, groundnut, corn, germ, olive,
castor and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and
mixtures thereof.
[0129] Suspensions, in addition to the subject composition, may
contain suspending agents such as, for example, ethoxylated
isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0130] Formulations for rectal or vaginal administration may be
presented as a suppository, which may be prepared by mixing a
subject composition with one or more suitable non-irritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the body cavity and release the active
agent. Formulations which are suitable for vaginal administration
also include pessaries, tampons, creams, gels, pastes, foams or
spray formulations containing such carriers as are known in the art
to be appropriate.
[0131] Dosage forms for transdermal administration of a subject
composition includes powders, sprays, ointments, pastes, creams,
lotions, gels, solutions, patches and inhalants. The active
component may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0132] The ointments, pastes, creams and gels may contain, in
addition to a subject composition, excipients, such as animal and
vegetable fats, oils, waxes, paraffins, starch, tragacanth,
cellulose derivatives, polyethylene glycols, silicones, bentonites,
silicic acid, talc and zinc oxide, or mixtures thereof.
[0133] Powders and sprays may contain, in addition to a subject
composition, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays may additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0134] Compositions of the present invention may alternatively be
administered by aerosol. This is accomplished by preparing an
aqueous aerosol, liposomal preparation or solid particles
containing the compound(s). A non-aqueous (e.g., fluorocarbon
propellant) suspension could be used. Sonic nebulizers may be used
because they minimize exposing the agent to shear, which may result
in degradation of the compounds contained in the subject
compositions.
[0135] Ordinarily, an aqueous aerosol is made by formulating an
aqueous solution or suspension of a subject composition together
with conventional pharmaceutically acceptable carriers and
stabilizers. The carriers and stabilizers vary with the
requirements of the particular subject composition, but typically
include non-ionic surfactants (Tweens, Pluronics, or polyethylene
glycol), innocuous proteins like serum albumin, sorbitan esters,
oleic acid, lecithin, amino acids such as glycine, buffers, salts,
sugars or sugar alcohols. Aerosols generally are prepared from
isotonic solutions.
[0136] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise a subject composition in
combination with one or more pharmaceutically-acceptable sterile
isotonic aqueous or non-aqueous solutions, dispersions, suspensions
or emulsions, or sterile powders which may be reconstituted into
sterile injectable solutions or dispersions just prior to use,
which may contain antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0137] Examples of suitable aqueous and non-aqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity may be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0138] Pharmaceutical formulations may also be extended or delayed
release formulations where the active agents are released over an
extended period of time.
Dosages
[0139] Administration of the compositions of the present invention
will be in an amount sufficient to achieve a therapeutic effect as
recognized by one of ordinary skill in the art.
[0140] The dosage of any compositions of the present invention will
vary depending on the symptoms, age and body weight of the patient,
the nature and severity of the disorder to be treated or prevented,
the route of administration, and the form of the subject
composition. Any of the subject formulations may be administered in
a single dose or in divided doses. Dosages for the compositions of
the present invention may be readily determined by techniques known
to those of skill in the art or as taught herein.
[0141] In certain embodiments, the dosage of the subject compounds
will generally be in the range of about 0.01 ng to about 10 g per
kg body weight, specifically in the range of about 1 ng to about
0.1 g per kg, and more specifically in the range of about 100 ng to
about 10 mg per kg.
[0142] An effective dose or amount, and any possible affects on the
timing of administration of the formulation, may need to be
identified for any particular composition of the present invention.
This may be accomplished by routine experiment as described herein,
using one or more groups of animals (preferably at least 5 animals
per group), or in human trials if appropriate. The effectiveness of
any subject composition and method of treatment or prevention may
be assessed by administering the composition and assessing the
effect of the administration by measuring one or more applicable
indices, and comparing the post-treatment values of these indices
to the values of the same indices prior to treatment.
[0143] The precise time of administration and amount of any
particular subject composition that will yield the most effective
treatment in a given patient will depend upon the activity,
pharmacokinetics, and bioavailability of a subject composition,
physiological condition of the patient (including age, sex, disease
type and stage, general physical condition, responsiveness to a
given dosage and type of medication), route of administration, and
the like. The guidelines presented herein may be used to optimize
the treatment, e.g., determining the optimum time and/or amount of
administration, which will require no more than routine
experimentation consisting of monitoring the subject and adjusting
the dosage and/or timing.
[0144] While the subject is being treated, the health of the
patient may be monitored by measuring one or more of the relevant
indices at predetermined times during the treatment period.
Treatment, including composition, amounts, times of administration
and formulation, may be optimized according to the results of such
monitoring. The patient may be periodically reevaluated to
determine the extent of improvement by measuring the same
parameters. Adjustments to the amount(s) of subject composition
administered and possibly to the time of administration may be made
based on these reevaluations.
[0145] Treatment may be initiated with smaller dosages which are
less than the optimum dose of the compound. Thereafter, the dosage
may be increased by small increments until the optimum therapeutic
effect is attained.
[0146] The use of the subject compositions may reduce the required
dosage for any individual agent contained in the compositions
(e.g., the steroidal anti inflammatory drug) because the onset and
duration of effect of the different agents may be
complimentary.
[0147] Toxicity and therapeutic efficacy of subject compositions
may be determined by standard pharmaceutical procedures in cell
cultures or experimental animals, e.g., for determining the
LD.sub.50 and the ED.sub.50.
[0148] The data obtained from the cell culture assays and animal
studies may be used in formulating a range of dosage for use in
humans. The dosage of any subject composition lies preferably
within a range of circulating concentrations that include the
ED.sub.50 with little or no toxicity. The dosage may vary within
this range depending upon the dosage form employed and the route of
administration utilized. For compositions of the present invention,
the therapeutically effective dose may be estimated initially from
cell culture assays.
[0149] In general, the doses of an active agent will be chosen by a
physician based on the age, physical condition, weight and other
factors known in the medical arts.
Efficacy of Treatment
[0150] The efficacy of treatment with the subject compositions may
be determined in a number of fashions known to those of skill in
the art.
[0151] In one exemplary method, the median rate of decrease in
inflammation for treatment with a subject composition may be
compared to other forms of treatment with the particular
cardiovascular agent contained in the subject composition, or with
other cardiovascular agents. The decrease in inflammation for
treatment with a subject composition as compared to treatment with
another method may be 10, 25, 50, 75, 100, 150, 200, 300, 400%
greater or even more. The period of time for observing any such
decrease may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours.
The comparison may be made against treatment with the particular
cardiovascular agent contained in the subject composition, or with
other cardiovascular agents, or administration of the same or
different agents by a different method, or administration as part
of a different drug delivery device than a subject composition. The
comparison may be made against the same or a different effective
dosage of the various agents.
[0152] Alternatively, a comparison of the different treatment
regimens described above may be based on the effectiveness of the
treatment, using standard indices known to those of skill in the
art. One method of treatment may be 10%, 20%, 30%, 50%, 75%, 100%,
150%, 200%, 300% more effective, than another method.
[0153] Alternatively, the different treatment regimens may be
analyzed by comparing the therapeutic index for each of them, with
treatment with a subject composition as compared to another regimen
having a therapeutic index two, three, five or seven times that of,
or even one, two, three or more orders of magnitude greater than,
treatment with another method using the same or different
cardiovascular agents.
Kits
[0154] This invention also provides kits for conveniently and
effectively implementing the methods of this invention. Such kits
comprise any subject composition, and a means for facilitating
compliance with methods of this invention. Such kits provide a
convenient and effective means for assuring that the subject to be
treated takes the appropriate active in the correct dosage in the
correct manner. The compliance means of such kits includes any
means which facilitates administering the actives according to a
method of this invention. Such compliance means include
instructions, packaging, and dispensing means, and combinations
thereof. Kit components may be packaged for either manual or
partially or wholly automated practice of the foregoing methods. In
other embodiments involving kits, this invention contemplates a kit
including compositions of the present invention, and optionally
instructions for their use.
EXEMPLIFICATION
Example 1
Measurements of NO Release from Human Endothelium
[0155] All measurements presented were recorded in vitro using a
sensitive porphyrinic probe, as previously described. Malinski T,
Taha Z., Nature. 1992; 358:676-678; Malinski T, Czuchajowski L.,
Methods in Nitric Oxide Research. 1996:319-339. NO release was
measured directly from HUVEC. HUVEC cells from Black and White
donors were grown in Ham's F12K medium with 2 mM L-glutamine
adjusted to contain 1.5 g/L sodium bicarbonate and supplemented
with 0.1 mg/ml heparin and 0.03-0.05 mg/ml endothelial cell growth
supplement (ECGS)+10% fetal bovine serum. The HUVEC cells were kept
in an atmosphere of elevated CO2 concentration (5%). Nebivolol was
obtained from Mylan Laboratories (Morgantown, W. Va.).
[0156] All measurements of endothelial NO release were conducted in
Hank's balance solution at 37.degree. C. Cell wells were
transferred to a Faraday cage and a porphyrinic sensor (diameter
0.5 mm) was positioned at a distance of 5.+-.2 .mu.m from the
surface of the endothelial cells using an inverted microscope
(Leica Microsystems, Wetzlar, Germany) and a computer-assisted
micromanipulator. The sensor operated with a three-electrode
system: nanosensor (working electrode), saturated calomel electrode
(reference electrode) and platinum wire (counter electrode, 0.5 mm
diameter). The three electrodes were connected to a
potentiostat/galvanostat PAR273. The baseline was stabilized after
about 20 seconds. The test compounds were injected with a
nanoinjector onto the surface of the cells following solubilization
in buffer. Cells were incubated with the test compounds for a
24-hour period. The compounds were then washed out of the system
before being immediately reintroduced in order to evaluate the
consequences of chronic treatment on NO release from the cells. For
additive experiments, cells were incubated with ACE inhibitor for
24 hours, the inhibitor was washed out of the system, nebivolol was
added and the NO release measured. The current proportional to the
NO concentration was measured with the sensor, which operated in
amperometric mode at a constant potential of 0.63V. Data were
acquired with the use of an IBM computer with custom software and
amperograms (current vs. time curves) were recorded with a Guniry
FAS1 Femtostat (Warminster, Pa.). Maximum release of NO was
produced using a calcium agonist (1 .mu.M). By increasing
cytoplasmic levels of calcium, the ion can bind to calmodulin. The
Ca2+-calmodulin complex is a cofactor for endothelial NO synthase,
along with FAD, FMN, Heme and BH4.
[0157] Nanosensors were prepared from carbon fibers. The size of
the tip of carbon fiber was reduced from 6 .mu.m to less than .mu.m
by temperature controlled burning. The sensors were sensitized to
NO by deposition of electrically conductive polymeric porphyrin and
covered with a thin layer of Nafion. The porphyrinic microsensor
has a response time of 0.1 ms at a micromolar NO concentration and
10 ms at the detection limit of 1 nM.
[0158] The nanosensor for NO was calibrated using saturated
solution (concentration 1.82 mM verified with the coulometric
method). Linear calibration curves were constructed for each sensor
from 5.times.10-9 to 3.times.10.sup.-6M NO before and after
measurements of cell activity. The concentration-dependent effects
of nebivolol and certain ACE-inhibitors on NO releasing capacity
were tested using a calcium ionophore (A23187) that stimulates NO
release, independently of G-protein-coupled receptors. The data
were presented as the mean.+-.SEM for each of the triplicate
measurements. The data (calculation and plotting) were transferred
to Microcal Origin Software (OriginLab Corp., Northampton,
Mass.).
[0159] The HUVEC preparation is stable over the course of these
experiments with the cells remaining viable in culture for >24
hours. Under non-stimulating conditions, basal levels of NO release
are very low (<30 nM). Measurement of NO release as a function
of treatment was conducted in individual endothelial cells.
Multiple measurements of NO release can be conducted on single
cells following a brief refractory period. For robust statistical
analysis, separate cells were used for each concentration and type
of drug used in these analyses.
[0160] In FIG. 1, the extent of NO release from Black and White
donors was measured after chronic treatment with the ACE inhibitor,
ramiprilat, followed by treatment with nebivolol (1 .mu.M). At
concentrations of 1, 5, and 10 .mu.M ramiprilat, there were modest
but significant effects in the ability of nebivolol to increase NO
release from Black and White donor endothelial cells. The magnitude
of the increase is greater in endothelial cells from Black
donors.
[0161] In FIG. 3, the extent of NO release from Black and White
donors was measured with nebivolol (1 .mu.M) following chronic
treatment with the ACE-inhibitor, enalapril. As observed with
ramiprilat (above), enalapril significantly enhanced the ability of
nebivolol to increase NO release at concentrations of 5 and 10
.mu.M and 1, 5 and 10 .mu.M in Black and White donor cells,
respectively. The magnitude of the increase is greater in
endothelial cells from Blacks than Whites (FIG. 4).
[0162] There were significant concentration dependent effects on
the ability of nebivolol to enhance NO release from Black and White
donor endothelial cells that had been chronically treated with ACE
inhibitors. Additionally, this property of the drug appears to work
independently of .beta.1-adrenoceptor blockade. By promoting a more
normal vascular physiology through an NO-dependent pathway,
nebivolol treatment may have better efficacy and fewer side effects
as compared to agents that only inhibit the sympathetic nervous
system. These data further support the hypothesis that nebivolol
may have distinct pharmacologic benefits through modulation of
endothelial function and NO metabolism.
INCORPORATION BY REFERENCE
[0163] All of the patents and publications cited herein are hereby
incorporated by reference.
EQUIVALENTS
[0164] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein.
* * * * *