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Researchers Submit Patent Application, "Intravenous Infusion of Curcumin and a Calcium Channel Blocker", for Approval

September 11, 2014



By a News Reporter-Staff News Editor at Women's Health Weekly -- From Washington, D.C., NewsRx journalists report that a patent application by the inventor Helson, Lawrence (Quakertown, PA), filed on April 30, 2014, was made available online on August 28, 2014 (see also SignPath Pharma Inc.).

The patent's assignee is SignPath Pharma Inc.

News editors obtained the following quote from the background information supplied by the inventors: "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.

"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.

"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.

"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."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventor's summary information for this patent application: "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.

"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.

"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.

"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.

"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.

"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.

"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.

"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.

"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.

"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.

"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."

For additional information on this patent application, see: Helson, Lawrence. Intravenous Infusion of Curcumin and a Calcium Channel Blocker. Filed April 30, 2014 and posted August 28, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=3293&p=66&f=G&l=50&d=PG01&S1=20140821.PD.&OS=PD/20140821&RS=PD/20140821

Keywords for this news article include: Alkanes, Biogenic Monoamines, Biological Factors, Blood Cells, Breast Cancer, Calcium Channels, Carrier Proteins, Catecholamines, Catechols, Curcumin, Cytokines, Diarylheptanoids, Drug Delivery Systems, Erythropoietin, Fluspirilene, Hydrocarbons, Ion Channels, Liposomes, Membrane Proteins, Mibefradil, Oncology, Organic Chemicals, Peptides, SignPath Pharma Inc., Spiro Compounds, Tetrahydronaphthalenes, Therapy, Women's Health.

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Source: Women's Health Weekly


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