U.S. patent application number 14/265669 was filed with the patent office on 2014-08-21 for intravenous infusion of curcumin and a calcium channel blocker.
This patent application is currently assigned to SignPath Pharma Inc.. The applicant listed for this patent is SignPath Pharma Inc.. Invention is credited to Lawrence Helson.
Application Number | 20140234402 14/265669 |
Document ID | / |
Family ID | 44011450 |
Filed Date | 2014-08-21 |
United States Patent
Application |
20140234402 |
Kind Code |
A1 |
Helson; Lawrence |
August 21, 2014 |
Intravenous Infusion of Curcumin and a Calcium Channel Blocker
Abstract
Compositions and methods for treating systemic diseases by
intravenous administration of formulations of synthesized curcumin
(diferuloylmethane) and concomitantly a calcium channel blocker to
human subjects with neoplastic and neurodegenerative diseases are
disclosed herein. The diseases are treated by prolonged
administration of sub-optimal doses of liposomal curcumin or
polymeric nanocurcumin or the sustained release curcumin from PLGA
nanocurcumin at dosages below systemic hemolytic thresholds
concomitantly with or without calcium channel blockers.
Inventors: |
Helson; Lawrence;
(Quakertown, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SignPath Pharma Inc. |
Quakertown |
PA |
US |
|
|
Assignee: |
SignPath Pharma Inc.
Quakertown
PA
|
Family ID: |
44011450 |
Appl. No.: |
14/265669 |
Filed: |
April 30, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12949897 |
Nov 19, 2010 |
8747890 |
|
|
14265669 |
|
|
|
|
61262745 |
Nov 19, 2009 |
|
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Current U.S.
Class: |
424/450 ;
514/211.07; 514/278; 514/352; 514/394; 514/428; 514/654; 514/679;
514/7.7 |
Current CPC
Class: |
A61K 9/1271 20130101;
A61K 31/12 20130101; A61P 27/02 20180101; A61K 9/5031 20130101;
A61P 25/00 20180101; A61P 27/12 20180101; A61P 25/16 20180101; A61K
45/06 20130101; A61K 9/0019 20130101; A61P 35/00 20180101; A61K
9/127 20130101; A61P 33/00 20180101; A61P 25/28 20180101 |
Class at
Publication: |
424/450 ;
514/679; 514/211.07; 514/394; 514/428; 514/278; 514/7.7; 514/352;
514/654 |
International
Class: |
A61K 31/12 20060101
A61K031/12; A61K 45/06 20060101 A61K045/06; A61K 9/127 20060101
A61K009/127 |
Claims
1. A formulated pharmaceutical composition comprising a
therapeutically effective amount of an intravenous formulation of
curcumin enveloped by a polylactic glycolic acid (PLGA) copolymer
and a layer of lipids to form a liposome.
2. The composition of claim 1, wherein the composition is adapted
for administration in a human subject for a treatment of one or
more proliferative selected from the group consisting of neoplastic
disorders, neurodegenerative diseases, drug induced tardif
dyskinesia, parasitic diseases and abnormal ophthalmic disorders
such as cataract and macular degeneration.
3. The composition of claim 2, wherein the neoplastic disorders
comprise breast cancer, uterine cancer, cervical cancer, ophthalmic
tumors, brain tumors, and pancreatic cancer.
4. The composition of claim 2, wherein the neurodegenerative
diseases comprise neuropathologic disorders, Parkinson's disease,
Alzheimer's disease (AD), senile dementia, vascular dementias,
Pick's disease, and Creutzfeldt-Jacobs disease.
5. The composition of claim 1, wherein the composition further
comprises one or more calcium channel blockers selected from at
least one of verapamil, ethylisopropylameloride, niflamic acid,
NPPB, dihydropyridines, phenylalkylamines, Benzothiozepines,
Diltiazem, nonselective blockers comprising mibefradil, bepridil,
fendeline, fluspirilene, catecholamines, and erythropoietin
agents.
6. The composition of claim 1, wherein the curcumin is a synthetic
curcumin.
7. The composition of claim 1, wherein the composition comprises
one or more optional pharmaceutically acceptable excipients,
diluents, extended or controlled release agents, lubricants,
preservatives or any combinations thereof.
8. The composition of claim 1, wherein the polymer further
comprises another polymer selected from at least one of polyesters,
polylactides, polyglycolides, polycaprolactones, polyanhydrides,
polyamides, polyurethanes, polyesteramides, polydioxanones,
polyacetals, polyketals, polycarbonates, polyorthocarbonates,
polyorthoesters, polyphosphoesters, polyphosphazenes,
polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,
polyalkylene succinates, poly(malic acid), poly(amino acids),
copolymers, terpolymers, and combinations or mixtures thereof.
9. A method comprising intravenous administration to a subject of a
therapeutically effective amount of an intravenous composition of
curcumin, wherein the synthesized curcumin is enveloped by a
polylactic glycolic acid (PLGA) copolymer and a layer of lipids to
form a liposome.
10. The method of claim 9, further comprising the step of providing
a calcium channel blocker prior to or concomitantly with the
synthesized curcumin.
11. The method of claim 10, wherein the one or more calcium channel
blockers are selected from the group consisting of verapamil,
ethylisopropylameloride, niflamic acid, NPPB, dihydropyridines,
phenylalkylamines, Benzothiozepines, Diltiazem, nonselective
blockers comprising mibefradil, bepridil, fendeline, fluspirilene,
catecholamines, and erythropoietin agents.
12. A method of treating a subject afflicted with one or more
proliferative disorders comprising the steps of: identifying the
subject in need of treatment against the one or more proliferative
disorders; and administering a therapeutically effective amount of
an intravenous formulation of curcumin enveloped by a polylactic
glycolic acid (PLGA) copolymer and a layer of lipids to form a
liposome sufficient to treat the proliferative disorder.
13. The method of claim 12, wherein the one or more proliferative
diseases comprise breast, uterine cervical, ophthalmic and
pancreatic cancer.
14. The method of claim 12, wherein the formulation mitigates a
curcumin induced red blood cell (RBC) hemolysis.
15. The method of claim 12, wherein the liposomal curcumin is
infused continuously for 1-72 hours weekly for four weeks, or for
24 hours every other day weekly for 12 doses in combination with a
calcium channel blocker.
16. The method of claim 12, wherein the liposomal curcumin is
infused for 1 hour weekly for four weeks in combination with a
calcium channel blocker.
17. The method of claim 12, further comprising the step of
providing a calcium channel blocker selected from at least one of
verapamil, ethylisopropylameloride, niflamic acid, NPPB,
dihydropyridines, phenylalkylamines, Benzothiozepines, Diltiazem,
nonselective blockers comprising mibefradil, bepridil, fendeline,
fluspirilene, catecholamines, and erythropoietin agents.
18. A method of treating one or more diseases or conditions in a
subject comprising the steps of: identifying the subject in need of
treatment against the disease or the condition; and administering a
therapeutically effective amount of an intravenous formulation of
curcumin enveloped by a polylactic glycolic acid (PLGA) copolymer
and a layer of lipids to form a liposome.
19. The method of claim 18, wherein the disease or the condition
comprises proliferative diseases selected from the group consisting
of breast cancer, uterine cancer, cervical cancer, ophthalmic
tumors, brain tumors, pancreatic cancer, neuropathologic disorders,
Parkinson's disease, drug induced tardif dyskinesia, parasitic
diseases, and abnormal ophthalmic disorders such as cataract and
macular degeneration.
20. A method of treating a tumor in a human subject comprising the
step of: identifying the subject in need of the treatment against
the tumor; and administering a therapeutically effective amount of
an intravenous formulation of curcumin enveloped by a polylactic
glycolic acid (PLGA) copolymer and a layer of lipids to form a
liposome to treat the tumor.
21. The method of claim 20, wherein the conjugate is adapted for
administration in situ into a breast for treatment of a ductal
carcinoma, into an aqueous humor of an eye for the treatment of a
retinoblastoma or uveal melanoma, for intravesicular administration
for the treatment of a bladder cancer or for direct application to
an uterine cervix marked by a dysplasia or a cancer.
22. A method of treating an ophthalmic tumor, an age related
condition comprising macular degeneration and cataract or both in a
subject comprising the step of: identifying the subject in need of
treatment against the tumor or the age related condition; and
administering a therapeutically effective amount of an intravenous
formulation of curcumin enveloped by a polylactic glycolic acid
(PLGA) copolymer and a layer of lipids to form a liposome for the
treatment of the tumor or the age related condition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/949,897 filed Nov. 19, 2010, which is a
non-provisional application of U.S. Provisional Application Ser.
No. 61/262,745 filed Nov. 19, 2009, the entire contents of which
are incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] This invention relates in general to the field of treatment
of neoplastic and neurodegenerative diseases, and more particularly
to the intravenous administration of formulations of synthesized
curcumin (diferuloylmethane) and concomitantly a calcium channel
blocker to human subjects in need of treatment against neoplastic
and neurodegenerative diseases. Particular reference is made to the
prolonged administration of liposomal curcumin, or polymeric
nanocurcumin or to the sustained release of curcumin from PLGA
nanocurcumin at dosages below systemic hemolytic thresholds
concomitantly with calcium channel blockers.
STATEMENT OF FEDERALLY FUNDED RESEARCH
[0003] None.
REFERENCE OF A SEQUENCE LISTING
[0004] None.
BACKGROUND OF THE INVENTION
[0005] Without limiting the scope of the invention, its background
is described in connection with the use and dosage forms of
chemotherapeutic agents and agents for treating neurodegenerative
diseases, including curcumin, curcumin analogues, and
derivatives.
[0006] Curcumin has been reported to react negatively with growth
receptors such as epidermal growth factor, bFGF, cytokine stimuli
such as tumor necrosis factor and elements of signaling pathways
including key components of proliferation; Survivin, Akt, DNA
telomerase, BCL-2, and activators of NF-kB.sup.5. In both tumoral
and normal tissues it acts as an antioxidant and contributes
towards maintaining the redox potential of cells. Oral
administration as an extract of the turmeric plant has been used in
traditional medicine for over two thousand years and is reported to
be devoid of toxicity and concomitantly systemic therapeutic
activity mainly because of water insolubility, intestinal and
hepatic inactivation causing negligible bioavailability to tissues
beyond the gastrointestinal tract. To overcome these limitations,
parenteral intravenous curcumin formulations with liposomes.sup.2,
polymers.sup.3 (n-isopropylacrylamide, N-vinylpyrrolidione and
acrylic acid) and polylactic glycolic acid copolymer.sup.4 are
being developed.
[0007] U.S. Pat. No. 7,723,515 issued to Dimauro (2010) discloses
the use of methylene blue, a curcumin hybrid for treating
Alzheimer's Disease. The '515 patent relates to the intranasal
administration of a formulation comprising an effective amount of
curcumin to the olfactory mucosa across the cribriform plate and
into the brain in order to treat a neurodegenerative disease, such
as AD.
[0008] U.S. Patent Application Publication No. 2006/0067998
(Kurzrock et al. 2006) provides compositions and methods for the
treatment of cancer, including pancreatic cancer, breast cancer and
melanoma, in a human patient. The methods and compositions of the
present invention employ curcumin or a curcumin analogue
encapsulated in a colloidal drug delivery system, preferably a
liposomal drug delivery system. Suitable colloidal drug delivery
systems also include nanoparticles, nanocapsules, microparticles or
block copolymer micelles. The colloidal drug delivery system
encapsulating curcumin or a curcumin analogue is administered
parenterally in a pharmaceutically acceptable carrier.
SUMMARY OF THE INVENTION
[0009] The present invention includes compositions and methods for
treating systemic diseases characterized by abnormal cellular
stimuli, pathologic responses to oxidants, cytokines, and growth
factors; leading to abnormal activation of signaling pathways,
protein synthesis and unfettered death or proliferation. Blocking
these pathways at one or more sites using curcumin was selected for
use in a therapeutic method.
[0010] In one embodiment the present invention discloses a
formulated pharmaceutical composition comprising: a therapeutically
effective amount of a synthesized curcumin (diferuloylmethane),
wherein the synthesized curcumin is enveloped by a polylactic
glycolic acid (PLGA) copolymer, a layer of lipids to form a
liposome, conjugated to one or more polymers or any combinations
thereof; and one or more calcium channel blockers, wherein the
composition mitigates a curcumin induced red blood cell (RBC)
hemolysis. The composition of the present invention is adapted for
an intravenous administration in a human subject for a treatment of
one or more proliferative selected from the group consisting of
neoplastic disorders, neurodegenerative diseases, drug induced
tardif dyskinesia, parasitic diseases and abnormal ophthalmic
disorders such as cataract and macular degeneration. In specific
aspects of the present invention the neoplastic disorders comprise
breast cancer, uterine cancer, cervical cancer, ophthalmic tumors,
brain tumors, and pancreatic cancer and the neurodegenerative
diseases comprise neuropathologic disorders, Parkinson's disease,
Alzheimer's disease (AD), senile dementia, vascular dementias,
Pick's disease, and Creutzfeldt-Jacobs disease.
[0011] In another aspect the one or more calcium channel blockers
are selected from the group consisting of verapamil,
ethylisopropylameloride, niflamic acid, NPPB, dihydropyridines,
phenylalkylamines, Benzothiozepines, Diltiazem, nonselective
blockers comprising mibefradil, bepridil, fendeline, fluspirilene,
catecholamines, and erythropoietin agents. In yet another aspect
the calcium channel blockers are administered prior to or
concomitantly with the synthesized curcumin. In one aspect the
composition comprises one or more optional pharmaceutically
acceptable excipients, diluents, extended or controlled release
agents, lubricants, preservatives or any combinations thereof.
[0012] In a related aspect the polymer is a biodegradable polymer
selected from the group consisting of polyesters, polylactides,
polyglycolides, polycaprolactones, polyanhydrides, polyamides,
polyurethanes, polyesteramides, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthocarbonates, polyorthoesters,
polyphosphoesters, polyphosphazenes, polyhydroxybutyrates,
polyhydroxyvalerates, polyalkylene oxalates, polyalkylene
succinates, poly(malic acid), poly(amino acids), copolymers,
terpolymers, and combinations or mixtures thereof. More
specifically, the polymer is an acrylic acid, a vinylpyrolidinome,
a N-isopropylacrylamide or combinations and modifications thereof.
In another related aspect the synthesized curcumin comprises
curcumin, curcumin analogues, curcumin derivatives, and any
combinations or modifications thereof.
[0013] In another embodiment the present invention provides a
method comprising intravenous administration to a subject of a
therapeutically effective amount of a formulated composition of
synthesized curcumin (diferuloylmethane), wherein the synthesized
curcumin is enveloped by a polylactic glycolic acid (PLGA)
copolymer, a layer of lipids to form a liposome, conjugated to one
or more polymers or any combinations thereof in combination with
one or more calcium channel blockers to mitigate intravenous
curcumin induced red blood cell (RBC) hemolysis. The polymer used
in the method of the present invention is an acrylic acid, a
vinylpyrolidinome, a N-isopropylacrylamide or combinations and
modifications thereof. In one aspect the calcium channel blockers
are administered prior to or concomitantly with the synthesized
curcumin. In another aspect the one or more calcium channel
blockers are selected from the group consisting of verapamil,
ethylisopropylameloride, niflamic acid, NPPB, dihydropyridines,
phenylalkylamines, Benzothiozepines, Diltiazem, nonselective
blockers comprising mibefradil, bepridil, fendeline, fluspirilene,
catecholamines, and erythropoietin agents.
[0014] In yet another embodiment the present invention provides a
method of treating a subject afflicted with one or more
proliferative disorders comprising the steps of: identifying the
subject in need of treatment against the one or more proliferative
disorders; and administering topically or systemically a
therapeutically effective amount of one or more formulations of a
synthesized curcumin, wherein the formulations comprise a
polylactic glycolic acid (PLGA-curcumin) copolymer enveloped
curcumin, a liposomal curcumin or a polymer conjugated curcumin
(nanocurcumin), wherein the formulation is administered in
combination with a calcium channel blocker and is administered in a
sustained and specific manner.
[0015] In one aspect the one or more proliferative diseases
comprise breast, uterine cervical, ophthalmic and pancreatic
cancer. In another aspect the formulation mitigates a curcumin
induced red blood cell (RBC) hemolysis. In a related aspect the
liposomal curcumin or nanocurcumin is infused continuously for 1-72
hours weekly for four weeks, or for 24 hours every other day weekly
for 12 doses in combination with a calcium channel blocker. In
another aspect the PLGA-curcumin is infused for 1 hour weekly for
four weeks in combination with a calcium channel blocker. In yet
another aspect the calcium channel blocker is selected from the
group consisting of verapamil, ethylisopropylameloride, niflamic
acid, NPPB, dihydropyridines, phenylalkylamines, Benzothiozepines,
Diltiazem, nonselective blockers comprising mibefradil, bepridil,
fendeline, fluspirilene, catecholamines, and erythropoietin agents.
In a specific aspect the polymer is an acrylic acid, a
vinylpyrolidinome, a N-isopropylacrylamide or combinations and
modifications thereof.
[0016] Embodiments of the present invention disclose a method of
treating one or more diseases or conditions in a subject comprising
the steps of: (i) identifying the subject in need of treatment
against the disease or the condition and (ii) administering a
therapeutic effective amount of at least one formulation of a
synthesized curcumin selected from the group consisting of
polylactic glycolic acid (PLGA-curcumin) copolymer enveloped
curcumin, a liposomal curcumin or a polymer conjugated curcumin
(nanocurcumin) in combination with a calcium channel blocker
selected from the group consisting of verapamil,
ethylisopropylameloride, niflamic acid, NPPB, dihydropyridines,
phenylalkylamines, Benzothiozepines, Diltiazem, nonselective
blockers comprising mibefradil, bepridil, fendeline, fluspirilene,
catecholamines, and erythropoietin agents. The disease or the
condition described hereinabove comprises proliferative diseases
selected from the group consisting of breast cancer, uterine
cancer, cervical cancer, ophthalmic tumors, brain tumors,
pancreatic cancer, neuropathologic disorders, Parkinson's disease,
drug induced tardif dyskinesia, parasitic diseases, and abnormal
ophthalmic disorders such as cataract and macular degeneration. The
method as described herein, further comprising the step of adding
curcumin formulations and a calcium channel blocker to autologous
bone marrow stem cell or peripheral blood stem cell preparations
prior to transplant into a recipient in order to eliminate viable
tumor cell contamination.
[0017] In another embodiment the present invention provides a
method for treating a tumor in a human subject comprising the step
of: identifying the subject in need of the treatment against the
tumor; and administering a therapeutically effective amount of a
polylactic glycolic acid (PLGA-curcumin) curcumin conjugate with or
without a calcium channel blocker directly into the tumor for
treating the tumor. In one aspect of the tumor treating method of
the present invention the curcumin is a synthesized curcumin,
comprising curcumin, a curcumin analogue, a curcumin derivative,
and any combinations or modifications thereof. In another aspect
the conjugate is adapted for administration in situ into a breast
for treatment of a ductal carcinoma, into an aqueous humor of an
eye for the treatment of a retinoblastoma or uveal melanoma, for
intravesicular administration for the treatment of a bladder cancer
or for direct application to an uterine cervix marked by a
dysplasia or a cancer.
[0018] Embodiments of the present invention also disclose a method
of treating an ophthalmic tumor, an age related condition
comprising macular degeneration and cataract or both in a subject
comprising the step of: identifying the subject in need of
treatment against the tumor or the age related condition; and
administering a therapeutically effective amount of a composition
adapted for ocular administration into the eye of the subject,
wherein the composition comprises a polylactic glycolic acid
(PLGA-curcumin) curcumin conjugate, a polymer conjugated curcumin
(nanocurcumin) or both with or without a calcium channel blocker
for the treatment of the tumor or the age related condition. The
curcumin used in the treatment method described above is a
synthesized curcumin, comprising curcumin, a curcumin analogue, a
curcumin derivative, and any combinations or modifications
thereof.
[0019] The invention provides a method for treating systemic
disorders in humans. The method comprises administering a
pharmaceutical composition intravenously as an intermittent
continuous infusion or sustained release during a 28 day treatment
cycle; which may be repeated depending upon tolerance, and
therapeutic need. By combining curcumin with a calcium channel
blocker hemolytic effects of curcumin are mitigated. The
compositions for use with the methods of the present invention
include, e.g., different formulations that enclose an effective
amount of curcumin, increases aqueous solubility, enhances delivery
to pathologic tissues, and protect curcumin from hepatic
inactivating enzymes. In mice, curcumin solubility limits the
intravenous injectable volume to a maximum dose of 250 mg/M.sup.2,
which does not indicate the upper limit of dosage. Liposomal
curcumin at 125 mg/M.sup.2 significantly inhibited growth of human
pancreatic xenografts in mice without toxicity.sup.8. A 140
mg/M.sup.2/dose would offer a similar dose intensity in humans
because of smaller human body surface area relative to weight. The
maximum tolerated dose marked by a brief reversible limited episode
of hemolysis and hematuria in four out of five 10 kg dogs infused
over one hour was 440 mg/M.sup.2. An 800 mg/M.sup.2 single dose in
dogs induced irreversible life-threatening hemolysis. In an 80 kg
human with a 5 liter blood volume, a 440 mg/M.sup.2 intravenous
infusion would exceed the maximum tolerated dose. To avoid toxicity
this invention teaches the intravenous route of administration of
curcumin formulations should be limited to low dosages at slow
infusion rates for liposomal curcumin, and polymeric nanocurcumin
or a sustained release of curcumin from a PLGA-nanocurcumin
formulations in combination with a calcium channel blocker.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] None.
DETAILED DESCRIPTION OF THE INVENTION
[0021] While the making and using of various embodiments of the
present invention are discussed in detail below, it should be
appreciated that the present invention provides many applicable
inventive concepts that can be embodied in a wide variety of
specific contexts. The specific embodiments discussed herein are
merely illustrative of specific ways to make and use the invention
and do not delimit the scope of the invention.
[0022] To facilitate the understanding of this invention, a number
of terms are defined below. Terms defined herein have meanings as
commonly understood by a person of ordinary skill in the areas
relevant to the present invention. Terms such as "a", "an" and
"the" are not intended to refer to only a singular entity, but
include the general class of which a specific example may be used
for illustration. The terminology herein is used to describe
specific embodiments of the invention, but their usage does not
delimit the invention, except as outlined in the claims.
[0023] The term "curcumin" as used herein refers to (diferuloyl
methane;
1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) a
naturally occurring compound which is the main coloring principle
found in the rhizomes of the plant Curcuma longa (U.S. Pat. No.
5,679,864 (Krackov et al.)). The term also includes any of those
structurally similar compounds encompassed by the term as
understood by those skilled in the art. The "curcumin" can be
natural or synthetic, and it can be present in any degree of purity
wherein it retains its characteristic coloring characteristics.
[0024] The term "calcium-channel blocker" or "Ca.sup.2+-channel
blocker" refers to one of a class of pharmacological agents, also
known as calcium antagonists, which inhibit the transmembrane flux
of calcium (Ca.sup.2) ions. "Calcium channel blockers" are also
known as calcium ion influx inhibitors, slow channel blockers,
calcium ion antagonists, calcium channel antagonist drugs and as
class IV antiarrhythmics.
[0025] The term "hemolysis" as used herein refers to a phenomenon
in which a membrane of an erythrocyte is broken and hemoglobin and
the like contained in the erythrocyte are release to the outside of
the erythrocyte.
[0026] As used herein the term "neoplastic disease or disorder"
refers to cancer as well as other diseases caused by malignant or
benign tumors. "Neoplastic diseases" are characterized by abnormal
tissue that shows partial or complete lack of structural
organization and functional coordination with normal tissue, and
usually forms a distinct mass which may be either benign or
malignant.
[0027] The term "neurodegenerative disease" as used herein
describes a disease or condition of the nervous system in which the
nervous system often deteriorates over time, thus impairing the
patient from carrying out normal tasks including motor tasks and
tasks related to cognition and/or memory. "Neurodegenerative
diseases" include, for example, Parkinson's disease, Huntington
disease, Alzheimer's disease and related disorders such as
amyotrophic lateral sclerosis, spinal muscular atrophy, Friedrich's
ataxia, Pick's disease, Bassen-Kornzweig syndrome, Refsom's
disease, retinal degeneration, Cruetzfelt-Jacob syndrome or prion
disease (mad cow disease), dementia with Lewy bodies,
schizophrenia, paraneoplastic cerebellar degeneration and
neurodegenerative conditions caused by stroke, among others.
[0028] The term "Alzheimer's disease" (abbreviated herein as "AD")
as used herein refers to a condition associated with formation of
neuritic plaques comprising, .beta.-amyloid protein primarily in
the hippocampus and cerebral cortex, as well as impairment in both
learning and memory. "AD" as used herein is meant to encompass both
AD as well as AD-type pathologies. As used herein, the term
"Parkinson's disease" refers to a neurological syndrome usually
resulting from a dopamine deficiency, resulting from degenerative,
vascular, or inflammatory changes in the basal ganglia of the
substantia nigra.
[0029] The term "macular degeneration" refers to any of a number of
conditions in which the retinal macula degenerates or becomes
dysfunctional, e.g., as a consequence of decreased growth of cells
of the macula, increased death or rearrangement of the cells of the
macula (e.g., RPE cells), loss of normal biological function, or a
combination of these events. Macular degeneration results in the
loss of integrity of the histoarchitecture of the cells and/or
extracellular matrix of the normal macula and/or the loss of
function of the cells of the macula. Examples of macular
degeneration-related disorder include AMD, North Carolina macular
dystrophy, Sorsby's fundus dystrophy, Stargardt's disease, pattern
dystrophy, Best disease, dominant drusen, and Malattia Leventinese
(radial drusen). The term also encompasses extramacular changes
that occur prior to, or following dysfunction and/or degeneration
of the macula. Thus, the term "macular degeneration" also broadly
includes any condition which alters or damages the integrity or
function of the macula (e.g., damage to the RPE or Bruch's
membrane). For example, the term encompasses retinal detachment,
chorioretinal degenerations, retinal degenerations, photoreceptor
degenerations, RPE degenerations, mucopolysaccharidoses, rod-cone
dystrophies, cone-rod dystrophies and cone degenerations.
[0030] As used herein the term "cataract" refers to any
opacification of the natural crystalline lens in the eye. Cataracts
cause loss of vision.
[0031] The term "liposome" as used herein refers to and includes
uni- and multi-lamellar vesicles and lipid emulsions. The
"liposome" is a capsule or a structure wherein the wall or membrane
thereof is formed of lipids, especially phospholipid, with the
optional addition therewith of a sterol, especially
cholesterol.
[0032] The term "in vivo" refers to within the body or in body
fluids that normally circulate entirely within the body within its
own protective skin, such as the blood, the lymph, or the
interstitial fluid. The term "in vitro" refers to a reaction/a
process/a phenomenon occurring outside of a body or a living
organism.
[0033] As used herein, the terms "subject" or "patient" are
intended to include living organisms that may have one or more
conditions referred to herein. Examples of subjects include humans,
monkeys, horses, cows, sheep, goats, dogs, cats, mice, rats, and
transgenic species thereof. Other examples of subjects include
experimental animals such as mice, rats, dogs, cats, goats, sheep,
pigs, and cows. A subject can be a human suffering from or
suspected of having, against a one or more proliferative
diseases.
[0034] The term "systemic administration" as used herein refers to
oral, sublingual, buccal, transnasal, transdermal, rectal,
intramuscular, intravenous, intraventricular, intrathecal, and
subcutaneous routes.
[0035] The term "intravenous administration" includes injection and
other modes of intravenous administration.
[0036] The terms "administration of" or "administering a" compound
refers to providing a compound of the invention to the individual
in need of treatment in a form that can be introduced into that
individual's body in a therapeutically useful form and
therapeutically useful amount, including, but not limited to: oral
dosage forms, such as tablets, capsules, syrups, suspensions, and
the like; injectable dosage forms, such as IV, IM, or IP, and the
like; transdermal dosage forms, including creams, jellies, powders,
or patches; buccal dosage forms; inhalation powders, sprays,
suspensions, and the like; and rectal suppositories.
[0037] Techniques and compositions for making useful dosage forms
using the present invention are described in one or more of the
following references: Ansel, Introduction to Pharmaceutical Dosage
Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th
ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in
Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds.,
1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton,
Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric
Coatings for Pharmaceutical Dosage Forms (Drugs and the
Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);
Pharmaceutical Particulate Carriers: Therapeutic Applications:
Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed.,
1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood
Books in the Biological Sciences. Series in Pharmaceutical
Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.);
Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40
(Gilbert S. Banker, Christopher T. Rhodes, Eds.), and the like,
relevant portions of each incorporated herein by reference.
[0038] As used herein, a "pharmaceutically acceptable" component is
one that is suitable for use with humans and/or animals without
undue adverse side effects (such as toxicity, irritation, and
allergic response) commensurate with a reasonable benefit/risk
ratio.
[0039] The terms "effective amount" or "therapeutically effective
amount" indicates the amount of the subject compound that will
elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher,
veterinarian, medical doctor or other clinician.
[0040] As used herein, the term "treatment" or "treating" includes
any administration of a compound of the present invention and
further includes (1) inhibiting the disease in an animal that is
experiencing or displaying the pathology or symptomatology of the
diseased (i.e., arresting further development of the pathology
and/or symptomatology), or (2) ameliorating the disease in an
animal that is experiencing or displaying the pathology or
symptomatology of the diseased (i.e., reversing the pathology
and/or symptomatology). The term "controlling" includes preventing
treating, eradicating, ameliorating or otherwise reducing the
severity of the condition being controlled.
[0041] This invention comprises a method for treating systemic
diseases characterized by abnormal cellular stimuli, pathologic
responses to oxidants, cytokines, and growth factors; leading to
abnormal activation of signaling pathways, protein synthesis and
unfettered death or proliferation. Blocking these pathways at one
or more sites is a preferred therapeutic method and, curcumin has
been chosen to accomplish this. To render the molecule soluble in
blood, and to avoid negligible bioavailability due to intestinal
wall and hepatic inactivation using the oral route, intravenous
liposomal, nanopolymeric, and PLGA curcumin formulations have been
devised. Toxicological studies in four dogs following a one hour
intravenous infusion at 440 mg/M.sup.2 revealed a single episode of
reversible red blood corpuscle or cell (RBC) hemolysis and
hematuria. Higher doses induced severe irreversible hemolysis.
Extrapolation to humans assuming human red blood corpuscles are
similarly sensitive to curcumin's hemolytic effects suggest an
infusion of less than 440 mg/M.sup.2 (C.sub.max of 160 ug/mL) would
fall below the RBC hemolytic threshold The hemolytic mechanism of
action is curcumin induced intracellular influx of calcium ions
which leads to RBC membrane rupture and consequent hemolysis. This
invention comprises an antidote for this action by pre- or
concomitant administration of a calcium channel blocker.
[0042] The invention is generally in the field of curcumin
administration, the active principle of the turmeric plant, which
has been synthesized to near purity (99.2%).sup.1. It is formulated
with liposomes.sup.2, polymers.sup.3, or PLGA.sup.4 to render it
capable of being administered intravenously as a bolus or as a
continuous infusion over 1-72 hours in combination with a calcium
channel blocker. Curcumin has antioxidant and anti-inflammatory
activity, and can block autonomous intracellular signaling pathways
abnormally responsive to extracellular growth factors, uncontrolled
proliferation of cells and fibrosis-associated and
tissue-degenerative conditions. Specifically, curcumin reacts
negatively with components of key signaling pathways commanding
proliferation, metabolism, survival and death. Oral and topical
administration of the extract of the turmeric plant has been used
in traditional medicine for over two thousand years. While oral
administration is devoid of systemic toxicity it is also devoid of
systemic therapeutic activity.sup.5. This is due to blood
insolubility, and intestinal wall and hepatic inactivation, i.e.,
it has negligible bioavailability for systemic diseases by the oral
route. To overcome these limitations, parenteral intravenous
curcumin formulations with liposomes.sup.2, polymers.sup.3
(n-isopropylacrylamide, N-vinylpyrrolidione and acrylic acid) and
polylactic glycolic acid copolymer were entered into in
pre-clinical drug development.sup.4.
[0043] The present invention allows curcumin to be used intravenous
with little or no hemolysis. Curcumin a food chemical present in
turmeric (Curcuma longa) has been considered to be
pharmacologically safe when taken by the oral route as an extract.
Beneficial responses in murine models of disease or murine models
incorporating xenotransplanted human tumors has been demonstrated
at nontoxic intravenous, or intraperitoneal, or oral dosages..sup.3
However, following synthesis of near pure curcumin (99.2%), and
during conduction of pre-clinical animal toxicity studies in dogs
evidence of dose dependent acute hemolysis was observed..sup.6 The
severity of hemolysis ranged from a single episode following a one
hour infusion of 400 mg/M.sup.2 to irreversible life threatening
hemolysis at 800 mg/M.sup.2. Significant hemolysis was observed
when these observations were extended to in vitro assays measuring
hemolysis of human red blood corpuscles following brief exposures
to low (less than 10 ug/ml) concentrations of liposomal curcumin.
These data indicate serious hemolytic issues, which prohibit
translational efficacy of intravenous curcumin treatment of
neoplastic, parasitic and tissue-degenerative diseases. More
importantly, these data contradict the implied assumption of safety
if curcumin is administered intravenously to dogs and to humans.
The current art is deficient in clinical strategies that allow
intravenous administration of curcumin. The dose finding trials
with the observed adverse hemolytic reactions in dogs are the first
reported..sup.9 Because the mechanism of RBC hemolysis is
intimately tied to Ca.sup.++ imbalance, the resolution for safe
administration, i.e. the present invention, consists of sustained
intravenous administration at sub-hemolytic dosages in combination
with correction of curcumin induced intracellular Ca++ imbalances
with a calcium blocking agent. This invention fulfills a need in
the art of translating important toxicological observations in in
vitro and animal models of disease to humans.
[0044] Dosage of intravenous curcumin: In human pancreatic tumor
xenografts in mice, the optimum intravenous dosage 125 mg/M.sup.2
(with a blood C.sub.max of 200 ug/ml) three times weekly for four
weeks.sup.8. In mice and rats no adverse events were observed in
dose-finding studies of intravenous liposomal curcumin at 250
mg/M.sup.2, the maximum injectable volume due to solubility
limitations. However, in three of four dogs, acute reversible
hemolysis and hematuria followed 440 mg/M.sup.2 liposomal curcumin
infused over one hour. At higher curcumin dosages acute hemolysis
was severe, and life threatening.sup.6. Extrapolating to humans and
assuming similar drug metabolism, distribution and pharmacokinetics
these data suggest that a 440 mg/M.sup.2 (blood C.sub.max of 160
ug/ml) one hour infusion of curcumin in an 80 kg human may induce
acute reversible hemolysis where the human RBC is more sensitive
than the dogs. This suggests that dosages inducing blood dosage and
C.sub.max be carefully titrated when developing intravenous
curcumin in any of the formulations. Comparison of dose/body weight
and dose/body surface area in mice, rats, dogs, and humans are
shown in Table I.
[0045] The mechanism of adverse reaction: The most probable
mechanism, but in no way a limitation of the present invention, by
which curcumin induces hemolysis is oxidation of calcium ATPase
reactive --SH groups which leads to complete inhibition of enzyme
activity, changes in Ca.sup.++ permeability ion channels, and
collapse of the gradient between external (10.sup.-3 M) and
intracellular (<10.sup.-5 M) calcium. This leads to enhanced
Ca.sup.++ influx.sup.12, which in turn induces phospholipid
perturbations of the red blood corpuscle outer membrane leading to
membrane lysis and hemolysis..sup.7 This invention proposes a
method to limit exacerbated Ca.sup.++ influx induced by curcumin
and thus to mitigate hemolytic effects from intravenous curcumin
administration by concomitant administration of a Ca.sup.++ channel
blocker. This would apply to twice weekly PLGA-nanocurcumin.sup.4,
a sustained-release formulation or slow intravenous infusions of
liposomal curcumin or polymeric nanocurcumin.
[0046] Rational for intravenous administration: Intravenous
administration of liposomal curcumin offers direct distribution to
pathologic tissues prior to passage and metabolism in the hepatic
circulation, and may permit preferential accumulation of active
principle in tumor or degenerated cells compared to normal cells.
These factors plus potential additional protection from hepatic
inactivation by the polymeric or sustained release PLGA
nanocurcumin formulations make this invention an improvement over
oral and topical methods of administration.sup.8, 9, 10. It is an
objective of the present invention to provide a protracted exposure
of curcumin and concomitantly a calcium channel blocker as a method
of treating humans with cell/tissue proliferative and
neurodegenerative disorders characterized by growth receptor and
signaling pathway dysfunctions.
[0047] Extrapolation from animal toxicology: In dogs one-hour
intravenous administration of liposomal curcumin at 440 mg/M.sup.2
(C.sub.max 200 ug/ml) was followed by reversible hemolysis within
24 hours. A single one-hour infusion of 800 mg/M.sup.2 (C.sub.max
400 ug/mL) liposomal curcumin was followed by irreversible
hemolysis and life threatening anemia.sup.6. Extrapolating to
humans from the dog, C.sub.max in the blood should not surpass
C.sub.max 200 ug/ml (following 300 mg/M.sup.2) to avoid hemolysis.
Curcumin induced hemolysis can theoretically be partially resolved
by sustained release from PLGA curcumin, or constant infusion of
liposomal or polymeric nanocurcumin dosages below 300 mg/M.sup.2.
In vitro hemolysis of RBC comparing liposomal curcumin and curcumin
in humans and dogs are presented in Table II.
[0048] Extrapolation from in vitro toxicity: Everett et al.,
reported turmeric extract (78% curcumin) at 1-10 uM (0.368-3.68
ug/ml) induced apoptosis in human cultured primary leukemic B-CLL
cells. The EC.sub.50 was optimal at 24-48 hours exposure..sup.11
Based upon these observations, in humans, 9 mg/M.sup.2
intravenously in an 80 kg person would produce a C.sub.max blood
level of 3.4 ug/ml. To achieve a steady state at this level,
assuming the T/2 in humans is three hours a 24 hour infusion of
liposomal curcumin or polymeric nanocurcumin, would require a 384
mg constant infusion concentration of liposomal curcumin infused
over 24 hours or longer. Infusions of this concentration and rate
will fall below the 10 ug/ml hemolytic dose, and below the
EC.sub.50 of 21.8 uM for non-malignant human mononuclear
cells.sup.11. Translating to the clinical level with PLGA curcumin
this invention proposes a four week treatment cycle with 2,700 mg
weekly. The rational for concomitant calcium channel blocker
administration is the differential in sensitivity to curcumin
effects on Ca.sup.++ influx in nucleated hematopoietic cells and
red blood corpuscles and one of several classes of calcium channel
blockers, which disrupt the conduction of calcium channels leading
to a decrease in intracellular calcium hence preventing the
initiation of the hemolysis cascade. The curcumin induction of
hemolysis is considered to be initiated by increased calcium ion
transport to the RBC interior following inhibition of
calcium.sup.++ ATPase. With the opening of the Ca.sup.++
permeability channels, the influx of Ca.sup.++ activates RBC
membrane scramblase leading to movement of phosphatidylserine to
the outer membrane leaflet. This is followed by RBC membrane lysis,
cell shrinkage and hemoglobin release. This invention teaches a
combination of sustained sub-hemolytic dosages of curcumin combined
with a calcium channel blocker to prohibit adverse hemolytic
effects.
TABLE-US-00001 TABLE I Comparison of dose/body weight and dose/body
surface area in mice, rats, dogs, and humans. Body Body Surface
Species Weight Area (M.sup.2) Mouse 20 grams 0.03 dosing at 40
mg/kg bolus = 0.8 mg/0.003 M.sup.2 = 250 mg/M.sup.2 dosing at 20
mg/kg bolus = 0.4 mg/0.003 M.sup.2 = 125 mg/M.sup.2 Rat 250 grams
0.035 dosing at 40 mg/kg bolus = 10 mg/0.035 M.sup.2 = 300
mg/M.sup.2 Dog 10 0.46 dosing at 40 mg/kg/hour = kilograms 400
mg/0.46 M.sup.2 = 800 mg/M.sup.2 dosing at 15 mg/kg/hour = 150
mg/0.46 M.sup.2 = 300 mg/M.sup.2 Human 80 1.8 dosing at 7.0
mg/kg/hour = kilograms 560 mg/1.8 M.sup.2 = 300 mg/M.sup.2 dosing
at 3.0 mg/kg/hour = 240 mg/1.8 M.sup.2 = 125 mg/M.sup.2
TABLE-US-00002 TABLE II In vitro hemolysis of RBC comparing
liposomal curcumin and curcumin. Curcumin Liposomal Curcumin-ETOH
(mcg) (mcg) 400 150 10 400 10 Human RBC % hemolysis 59.8 54.5 44
66.9 57.6 Canine RBC % hemolysis 30.4 3.3 2.7 4.2 0.5
[0049] Those skilled in the art will acknowledge readily that the
present invention is well designed to carry out the advantages of
intravenous curcumin formulations while avoiding hemolysis a
critical adverse reaction that will prohibit translation to human
diseases and conditions otherwise amenable to curcumin therapy. The
present methods and specific compounds described herein are
presently representative of preferred embodiments, are exemplary,
and are not intended as limitations on the scope of the invention.
Changes to this invention and other uses will occur to those
skilled in the art, which are encompassed within the spirit of the
invention as defined by the scope of the claims.
[0050] It is contemplated that any embodiment discussed in this
specification can be implemented with respect to any method, kit,
reagent, or composition of the invention, and vice versa.
Furthermore, compositions of the invention can be used to achieve
methods of the invention.
[0051] It will be understood that particular embodiments described
herein are shown by way of illustration and not as limitations of
the invention. The principal features of this invention can be
employed in various embodiments without departing from the scope of
the invention. Those skilled in the art will recognize, or be able
to ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of this invention
and are covered by the claims.
[0052] All publications and patent applications mentioned in the
specification are indicative of the level of skill of those skilled
in the art to which this invention pertains. All publications and
patent applications are herein incorporated by reference to the
same extent as if each individual publication or patent application
was specifically and individually indicated to be incorporated by
reference.
[0053] The use of the word "a" or "an" when used in conjunction
with the term "comprising" in the claims and/or the specification
may mean "one," but it is also consistent with the meaning of "one
or more," "at least one," and "one or more than one." The use of
the term "or" in the claims is used to mean "and/or" unless
explicitly indicated to refer to alternatives only or the
alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or." Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0054] As used in this specification and claim(s), the words
"comprising" (and any form of comprising, such as "comprise" and
"comprises"), "having" (and any form of having, such as "have" and
"has"), "including" (and any form of including, such as "includes"
and "include") or "containing" (and any form of containing, such as
"contains" and "contain") are inclusive or open-ended and do not
exclude additional, unrecited elements or method steps.
[0055] The term "or combinations thereof" as used herein refers to
all permutations and combinations of the listed items preceding the
term. For example, "A, B, C, or combinations thereof" is intended
to include at least one of: A, B, C, AB, AC, BC, or ABC, and if
order is important in a particular context, also BA, CA, CB, CBA,
BCA, ACB, BAC, or CAB. Continuing with this example, expressly
included are combinations that contain repeats of one or more item
or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so
forth. The skilled artisan will understand that typically there is
no limit on the number of items or terms in any combination, unless
otherwise apparent from the context.
[0056] As used herein, words of approximation such as, without
limitation, "about", "substantial" or "substantially" refers to a
condition that when so modified is understood to not necessarily be
absolute or perfect but would be considered close enough to those
of ordinary skill in the art to warrant designating the condition
as being present. The extent to which the description may vary will
depend on how great a change can be instituted and still have one
of ordinary skilled in the art recognize the modified feature as
still having the required characteristics and capabilities of the
unmodified feature. In general, but subject to the preceding
discussion, a numerical value herein that is modified by a word of
approximation such as "about" may vary from the stated value by at
least .+-.1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
[0057] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. All such similar substitutes and modifications apparent
to those skilled in the art are deemed to be within the spirit,
scope and concept of the invention as defined by the appended
claims.
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