奥地利专利AT515178A2 CURCUMIN-ER, A NANOCURCUMIN FROM LIPOSOMAL PLGA WITH CONTINUED RELEASE TO MINIMIZE QT EXTENSION TO C

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专利摘要:
The present invention includes compositions and methods of making a nanoparticle composition comprising a polymeric core containing at least one polymer and at least one active agent and at least one layer of at least one lipid on the surface of the polymeric core; In particular, the invention relates to the use of curcumin in such a lipid-polymer nanoparticle formulation to minimize QT prolongation associated with curcumin in the treatment of cancer.
公开号:AT515178A2
申请号:T9306/2013
申请日:2013-08-31
公开日:2015-06-15
发明作者:Amalendu Prakash Ranjan；Anindita Mukerjee；Jamboor K Vishwanatha；Lawrence Helson
申请人:Univ North Texas；
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FIELD OF THE INVENTION
The present invention relates generally to nanoparticles containing a polymeric core comprising at least one polymer and at least one active agent and at least one layer of at least one lipid on the surface of the polymeric core. In particular, the present invention relates to the use of curcumin in such a lipid-polymer nanoparticle formulation for minimizing QT prolongation in association with curcumin in the treatment of cancer.
GENERAL PRIOR ART
The prior art associated with the invention is described in connection with the delivery of pharmaceutical active ingredients, without restricting the scope of the invention. U.S. Patent 7,968,115 to Kurzrock (filed September 7, 2005) provides a composition and method for treating cancer, including pancreatic cancer, breast cancer, and melanoma, in a human patient. The methods and compositions of the present invention use curcumin or a curcumin analog encapsulated in a colloidal drug delivery system, preferably in a liposomal drug delivery system. Suitable colloidal drug delivery systems are also nanoparticles, nanocapsules, microparticles or block copolymer micelles. The curcumin or a curcumin analog encapsulating colloidal drug delivery system is administered parenterally in a pharmaceutically suitable carrier. U.S. Patent 8,202,839 to Sung (filed January 7, 2012) discloses a pharmaceutical composition of bioactive agent for oral delivery composed of chitosan, polyglutamic acid, and a bioactive agent. The chitosan-based nanoparticles are characterized by a positive surface charge and enhanced permeability to oral drug delivery.
The US Patent Application Publication No. 20120058208 by Jacob (synergistic composition for enhancing the bioavailability of curcumin) (filed March 8, 2012) relates to a composition for enhancing the
Bioavailability of curcumin. In one embodiment, a composition is provided which contains plant extracts of curcumin, vanilla and ginger, the extracts of ginger and vanilla being rich in gingerol and vanillin, respectively. In other embodiments, curcumin and at least one member selected from the group consisting of vanilla, ginger and capsaicin are provided.
US Patent Application Publication No. 20120003177 to Shen (curcumin-containing polymers and water-soluble curcumin derivatives as prodrugs of prodrug carriers) (filed on Jan. 5, 2012) describes curcumin, a polyphenol extracted from the turmeric rhizome, which polymerizes to prepare a polymeric material having a backbone of at least one repeating structural unit, at least one of which contains a curcumin monomer residue. These curcumin-containing polymers have a broad spectrum of pharmacological activities, including, but not limited to, tumor-inhibiting, antioxidant, anti-inflammatory, antithrombotic and antibacterial activities. Certain types of these polymers have considerable antitumor activity. Water-soluble curcumin derivatives and their use as prodrugs and prodrugs are also disclosed.
BRIEF DESCRIPTION OF THE INVENTION
Low solubility, low bioavailability, QT prolongation and rapid clearance in vivo are problems associated with curcumin. The benefits of liposomal nanocurcumin are not QT prolongation, high bioavailability, and low clearance in vivo, but the drawback is rapid release. The advantages of polymeric nanocurcumin are high bioavailability, sustained release, and little clearance in vivo, but the disadvantage is QT prolongation. The advantages of hybrid Nanocurcu-min are high bioavailability, sustained release, no QT prolongation, and little clearance in vivo.
The present invention includes methods and compositions comprising a polymeric nanoparticle core comprising at least one polymer and at least one active agent; and at least one layer of at least one lipid on the surface of the polymeric core. The at least one polymer may include PLGA um¬; and / or at least one polymer selected from the group consisting of poly (lactic acid), polylactide (PLA) and poly-L-lactide-co-s-caprolactone (PLCL). In certain forms, the at least one active ingredient comprises curcumin or a curcuminoid. The active ingredient may comprise at least one anticancer drug; and / or selected from at least one of an anticancer drug, an antibiotic, a viral, an antimycotic, an anthelmintic, a nutrient, a small molecule, a siRNA, an antioxidant, and an antibody. In certain forms, the nanoparticle composition does not cause QT prolongation. In certain aspects, the nanoparticle composition has high bioavailability. In certain aspects, the active agent may comprise a conventional radioisotope. The at least one active ingredient comprises a water-insoluble dye; and / or a metal nanoparticle for use as a contrast agent for MRI; and / or to select from the group containing Nile red, iron and platinum. In certain aspects, the at least one lipid comprises 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC); and / or di-myristoylphosphatidylglycerol (DMPG); 1,2-dioctadecanoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethylene glycol) (DSPE-PEG), DMPE-PEG] Maleimide, lecithin, cholesterol, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- (lisamine rhodamine-B-sulfonyl) (ammonium salt) and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N - (7-nitro-2-1,3-benzoxadiazol-4-yl) (ammonium salt). In various aspects, the nanoparticle composition may contain DMPC and DMPG in a molar ratio of 9: 1, 7: 3, 8: 2 or 7.5: 2.5. In certain aspects, the nanoparticles may comprise at least one targeting agent, wherein the taranting agent selectively and selectively brings the nanoparticle to diseased tissue / diseased cells, thereby minimizing the whole-body dose; and / or wherein the targeting agent contains an antibody or a functional fragment thereof capable of recognizing a target antigen; and / or selected from the group consisting of an antibody, a small molecule, a peptide, a carbohydrate, a siRNA, a protein, a nucleic acid, an aptamer, a second nanoparticle, a cytokine, a chemokine, a lymphokine, one
Receptor, a lipid, a lectin, a ferrous metal, a magnetic particle, a linker, an isotope or Kombina¬tionen consists thereof. In certain aspects, the nanoparticles have a size of 90 to 150 nm. The bioavailability of the drug may be increased, QT prolongation is re-engineered, and the drug may be released persistently.
The invention includes embodiments of methods of forming a nanoparticle composition which comprises forming an organic phase by combining at least one polymer, at least one solvent, and at least one active agent; Forming an aqueous lipid phase by mixing at least one lipid with water; Mixing the organic phase with the aqueous lipid phase to form an emulsion; and incubating the emulsion with self-assembly of nanoparticles. The at least one polymer may comprise PLGA; and / or at least one polymer selected from the group consisting of poly (lactic acid), polylactide (PLA) and poly-L-lactide-co-s-caprolactone (PLCL). The organic phase may contain PLGA at a concentration of 2-90 mg / ml and / or curcumin at a concentration of 1-15% w / v. In various aspects, at least one solvent may be an organic solvent; Acetoni¬tril; at least one solvent selected from the group consisting of acetone, tert-butyl alcohol, dimethylformamide and hexafluoroisopropanol. The at least one active ingredient comprises curcumin or a curcuminoid; and / orat least one anti-cancer drug; and / or a conventional radioisotope; and / or at least one active agent selected from the group comprising Nile Red, iron and platinum. In certain aspects, the at least one lipid may include DMPC; and / or DMPG and / or at least one lipid selected from the group consisting of 1,2-dioctadecanoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn- glycero-3-phosphoethanolamine N- [amino (polyethylene glycol) (DSPE-PEG), DMPE-PEG-maleimide, lecithin, cholesterol, 1,2-dimethystoyl-sn-glycero-3-phosphoethanolamine-N- (lisamine rhodamine) B-sulfonyl) (ammonium salt) and 1,2-dimyristoyl-sn-glycero-3-phos-ethanolamine N- (7-nitro-2-l, 3-benzoxadiazol-4-yl) (ammonium salt). In certain aspects, the at least one lipid comprises DMPC and DMPG in a molar ratio of 9: 1, 7: 3, 8: 2, 7.5: 2.5. In certain aspects, mixing the organic phase with the aqueous lipid phase involves slowly stirring the organic phase into the aqueous lipid phase; and / or mixing the organic phase with the aqueous lipid phase involves vortexing; and / or mixing the organic phase with the aqueous lipid phase further includes sonicating. In certain aspects, incubating the emulsion involves stirring the emulsion for 2 hours. In certain aspects, the method may further include separating the nanoparticles after incubating the emulsion; and / or filtering the nanoparticles after incubating the emulsion; and / or freezing the nanoparticles; and / or lyophilizing the nanoparticles; and / or attaching a targeting agent to the nanoparticles; and / or attaching at least one targeting agent, wherein the targeting agent selectively and selectively brings the nanoparticle to diseased tissue / cells, thereby minimizing a whole body dose; and / or attaching at least one targeting agent to the nanoparticles, wherein the targeting agent contains an antibody or functional fragment thereof capable of recognizing a target antigen. In certain embodiments, the nanoparticles have a size of 90 to 150 nm.
The invention includes embodiments of pharmaceutical compositions containing a drug delivery nanoparticle comprising a polymer, an active agent, and at least one layer of at least one lipid encapsulating the polymer and the drug.
The invention includes embodiments for treating a patient suspected of having a disease involving the administration of nanoparticles, said nanoparticles containing a polymeric core comprising at least one polymer and at least one active agent and at least one layer of at least one lipid on the surface of the polymeric core. In certain aspects, administration of nanoparticles involves administering the nanoparticle by intramuscular, subcutaneous, intravascular or intravenous administration. The disease may be selected from the group consisting of neurological, oncological and metabolic diseases; and / or from the group resulting from Parkinson's disease, Alzheimer's disease, multiple sclerosis, ALS, one
Sequelae, behavioral and cognitive disorders, a disease of the autistic spectrum, depression and neoplastic disease; and / or cancer. In certain forms of the active substance is released persistently.
The invention includes embodiments of a composition containing a polymeric nanoparticle core containing at least one polymer and curcumin and at least one layer of at least one lipid on the surface of the polymeric core.
The invention includes embodiments of forming a nanoparticle composition comprising forming an organic phase by combining at least one polymer, at least one solvent, and curcumin; Forming an aqueous lipid phase by mixing at least one lipid with water; Mixing the organic phase with the aqueous lipid phase to form an emulsion; and incubating the emulsion, wherein self-assembly of nanoparticles occurs.
The invention includes embodiments of pharmaceutical compositions containing a nanoparticle for drug delivery comprising a polymer, curcumin, and at least one layer of at least one lipid encapsulating the polymer and the drug.
The invention includes embodiments for treating a patient suspected of having a disease, the method comprising administering nanoparticles, wherein the nanoparticles contain a polymeric core, the at least one polymer, curcumin, and at least one layer of at least one lipid on the surface of the polymeric core.
Another embodiment includes a composition for treating cancer, comprising: a polymeric nanoparticle core comprising at least one polymer and at least one of curcumin or curcuminoids; and at least one layer of at least one lipid on the surface of the polymeric core, wherein the composition does not cause QT prolongation when an individual is provided with it. In one aspect, the at least one polymer comprises at least one of poly (lactic acid-co-glycolic acid) (PLGA), poly (lactic acid), polylactide (PLA), or poly-L-lactide-co-s-caprolactone (PLCL).
Another embodiment includes a method of forming a nanoparticle composition, comprising: forming an organic phase by combining at least one polymer, at least one solvent, and at least one of curcumin or curcuminoids; Forming an aqueous lipid phase by mixing at least one lipid with water; Mixing the organic phase with the aqueous lipid phase to form an emulsion; and incubating the emulsion, wherein self-assembly of nanoparticles takes place and wherein the curcumin or curcuminoid nanoparticles cause no QT prolongation when provided to an individual.
Another embodiment includes a method of treating a patient suspected of having a disease, the method comprising administering nanoparticles, the nanoparticles containing a polymeric core comprising at least one polymer and at least one active agent and at least one layer of at least one lipid on the surface of the polymeric core, which agent is intended to cause QT prolongation when provided to a subject. In one aspect, the method also includes the step of administering the nanoparticle by intramuscular, subcutaneous, intravascular or intravenous administration.
Another embodiment includes a method of forming a nanoparticle composition that prevents the agent from causing QT prolongation, comprising: forming an organic phase by combining at least one polymer, at least one solvent, and the drug that causes QT prolongation; Forming an aqueous lipid phase by mixing at least one lipid with water; Mixing the organic phase with the aqueous lipid phase to form an emulsion; and incubating the emulsion, wherein a self-assembly of nanoparticles takes place.
Another embodiment includes a pharmaceutical agent comprising: a nanoparticle for drug delivery, comprising a polymer, an agent that causes QT prolongation, and at least one layer of at least one lipid encapsulating the polymer and drug and causing the agent no QT extension.
Another embodiment includes a method of treating a patient suspected of having a disease, the method comprising administering nanoparticles, the nanoparticles containing a polymeric core comprising at least one polymer, curcumin, and at least one layer of at least one lipid on the surface of the polymeric nuclei, wherein treating the patient does not cause QT prolongation.
In another embodiment, the method for treating an individual suspected of having cancer includes: identifying that a patient is believed to have cancer; and providing an individual with an amount of at least one of curcumin or curcuminoids in an amount sufficient to reduce the cancer in the individual, wherein the at least one of curcumin or curcuminoids resides in a polymeric nanoparticle core comprising at least one polymer and at least one of curcumin or curcuminoids and at least one layer of at least one lipid on the surface of the polymeric core, wherein the at least one of the curcumin or curcuminoid nanoparticles does not cause QT prolongation when provided to an individual. In one aspect, the cancer is a pancreatic, prostate or breast cancer.
BRIEF DESCRIPTION OF THE DRAWINGS For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention, together with the accompanying drawings, in which:
Figure 1 illustrates the basic concept of the formation of hybrid nano-curcumin (HNC); Lipid DMPC and DMPG. Problems associated with curcumin are low solubility, low bioavailability, QT prolongation, and rapid clearance in vivo. The advantages of liposomal nanocurcumin are not QT prolongation, high bioavailability, and low clearance in vivo, but the disadvantage is the rapid release. The advantages of polymeric nanocurcumin are high bioavailability, sustained release, and low clearance in vivo, but the disadvantage is QT prolongation. The advantages of hybrid nanocurcumin are high bioavailability, sustained release, no QT prolongation, and little clearance in vivo.
Figure 2 shows the improved dispersibility of HNC in water.
Figure 3 represents transmission electron micrographs of HNC. The TEM scan shows HNC as a uniformly sized, nested, smooth nanoparticle.
Figures 4A and 4B: Figure 4A shows formulations of hybridna-nocurcumin (HNC). Four different formulations of HNC are shown using different ratios of DMPC and DMPG. FIG. 4B shows the particle size distribution in charge 3.
Figure 5 shows the HNC characterization, including average particle size, drug load, and encapsulation efficiency.
Figure 6 shows the hERG current density analysis of curcumin; li¬po somalem curcumin; and PLGA curcumin.
Figure 7 shows the hERG current density analysis of liposomes + curcumin; and liposomes.
Figure 8 shows the intracellular uptake of HNC in Mia PaCa cells.
Figure 9 shows a Western Blot analysis of MiaPaCa cells after treatment with hybrid nanocurcumin (25 μM (micromolar)).
Lane 1: untreated; Lane 2: blank nanoparticles; Lane 3: curcumin (24 hrs); Train 4: HNC (24 hours) and; Train 5 HNC (48h).
Figure 10 shows the vitality of MTT cells using HNC and a pancreatic cancer cell line (MiaPaCa cell line) after 48 hours.
FIG. 11 shows the protocol of the pulses or the original data acquisition design: detection rate (s): 1.0 kHz
Figure 12 shows the effect of lot A on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 13 shows the effect of lot A on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 14 shows the relationship (I-V) of the hERG current amplitude of transfected HEK293 cells exposed to lot A.
Figure 15 shows the effect of lot B on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 16 shows the effect of lot B on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 17 shows the relationship (I-V) of the hERG current amplitudes of transfected HEK293 cells exposed to lot B.
Figure 18 shows the effect of lot C on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 19 shows the effect of Lot C on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 20 shows the relationship (I-V) of hERG current amplitudes of transfected HEK293 cells exposed to lot C.
FIG. 21 shows the effect of charge D on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 22 shows the effect of Lot D on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 23 shows the relationship (I-V) of the hERG current amplitude of transfected HEK293 cells exposed to lot D.
Figure 24 shows the effect of lot E on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 25 shows the effect of Lot E on the hERG current density of transfected HEK293 cells at 20 mV.
Figure 26 shows the relationship (I-V) of the hERG current amplitudes of transfected HEK293 cells exposed to lot E.
Figure 27 shows the effect of tested compounds on the hERG current density at +20 mV.
Figure 28 shows the results of treatment of breast cancer in a cancer xenograft mouse model system.
Figure 29 shows additional results of the treatment of another breast cancer in a cancer xenograft mouse model system.
DESCRIPTION OF THE INVENTION While the preparation and use of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention contemplates 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 possibilities for making and using the invention and do not limit the scope of the invention.
Numerous terms are defined below in order to better understand the invention. The meanings of the terms defined herein are those as commonly understood by one of ordinary skill in the art to be relevant to the present invention. Handles such as "a," "a," "a," and "a " and "the", "the", "the " should not only refer to a singular unit, but include the general class from which a definite example may be used for illustration. The terminology herein is used to describe certain embodiments of the invention, but its use does not limit the invention except as described in the claims.
Problems associated with curcumin are low solubility, low bioavailability, QT prolongation, and rapid clearance in vivo. The advantages of liposomal nanocurcumins are not QT prolongation, high bioavailability, and little clearance in vivo, but the disadvantage is rapid release. The advantages of polymeric nanocurcumin are high bioavailability, sustained release, and low clearance in vivo, but the disadvantage is QT prolongation. The advantages of hybrid nanocurcumin are high bioavailability, sustained release, no QT prolongation, and little clearance in vivo.
A requirement in commercial drug development is the testing of drug effects on hERG (Ikr) in in vitro assays using transfected KEK293 cells. The present inventors determined the anti-hERG activity of curcumin (diferuloylmethane) in DMSO and three formulated curcumin Compounds: liposomal curcumin, nanocurcumin and a sustained release PLGA curcumin. The present inventors recognize that the K + current IC50 of curcumin formulated in DMSO is 3.4 μΜ. In the context of the current clinical phase-la-pharmacokinetics in normal individuals, the blood plasma level after a two-hour infusion of 4.5 mg / kg in the range of 5 to 11 μΜοΜ, it is considered that intravenous or subcutaneous curcumin formulations for therapeutic applications may inhibit IKr, lead to torsade de point arrhythmias, and possible clinical mortality. However, neither the liposomal nor the nanocurcumin formulation at 12 μΜοΙ has this effect on the K + channel. Co-administration of empty liposomes with curcumin was equally effective in preventing hERG blockade, but the PLGA-curcumin formulation did not have this effect.
These observations form a basis for (the construction of a novel curcumin formulation) a novel curcumin formulation consisting of liposome and PLGA which allows sustained release of curcumin without the concomitant inhibitory effects of curcumin on the cardiac K + channel.
The treatment of cancer is limited by the side effects of anti-cancer drugs. Chemotherapy is the only available option for the treatment of advanced cancers. However, the increasing number of indications of drug resistance and the nonspecific toxicity of these agents limit their therapeutic results. To solve this problem, it is important to deliver the drug in the proper amount to the site where the cancer is found in the body. A novel way of approaching this problem is through targeted drug delivery systems that deliver the drug preferably to the cancer site. In certain embodiments, targeted delivery molecules (targeting molecules, eg, antibodies) are used which recognize the cancer cells and bring the drug containing minute accumulated particles (nanoparticles) to the cancerous cells.
In certain embodiments, at least one tarantizing agent is attached to the nanoparticles, the targeting agent containing an antibody or functional fragment thereof capable of recognizing a target antigen. The targeting agents can be attached by insertion of a hetero / homobifunctional spacer capable of reacting with amines of lipids and targeting moieties.
Curcumin is a potent anticancer agent and has been used for several decades for its pharmacological activity. However, the major problems associated with curcumin are (1) low systemic bioavailability after any mode of administration; (2) QT prolongation when curcumin is administered alone; and (3) rapid in vivo elimination of curcumin. The present inventors solved these problems by formulating curcumin (99% pure) in a hybrid nanoformulation. See Figure 1.
The present inventors recognized that nanoformulation provides the solution to increase bioavailability and that a liposome formulation of curcumin produces virtually no QT prolongation. However, such formulations lack stability and have a certain inherent toxicity at higher doses. The present invention recognizes that curcumin is rapidly eliminated upon administration to animal models.
The present inventors have developed a nanoformulation system that increases the bioavailability of curcumin, minimizes QT prolongation, and releases the drug curcumin on an ongoing basis.
The hybrid nanocurcumin (HNC) system is a hybrid of lipids and polymer, with the polymeric core encapsulating curcumin.
The lipid is present as a continuous layer on the surface of the polymeric nanoparticle. In other words, the lipid envelops the polymeric nanoparticle. The lipid component of the hybridopanocurcinum helps to reduce QT elongation, while the polymeric core of the hybrid system allows sustained release of curcumin. The
Hybrid nanocurcumin (HNC) system solved all the above problems, i. H. (1) bioavailability of curcumin, (2) curcumin-induced QT prolongation and (3) simultaneous sustained release of curcumin.
The hybrid nanocurcumin (HNC) system has the following advantages: (1) the in vivo bioavailability of drugs (eg, curcumin) is improved; (2) the lipid component of hybrid nanocure cumin reduces QT prolongation; (3) the polymeric core of the hybrid system allows sustained release of the agent (eg, curcumin); (4) the formulation itself is a simple, practical, one-step process; and (5) this system can be used to formulate another similar type of drugs or drugs containing hydrophobic molecules. Examples would include curcumin analogues, docetaxel, paclitaxel, etc.
Due to the improved bioavailability and reduced side effects, the commercial potential of hybrid nanocurcate formulations is enormous.
One embodiment is a liposomal curcumin-PLGA compound with sustained release to prevent and treat neurological, oncological or metabolic diseases (hybrid nanocurcumin formulation).
Certain embodiments may be described as intravenous and / or subcutaneous administration of a novel formulation of syn thetcated curcumin (diferuloylmethane) bound to PLGA and a liposome. Such a formulation is designed to provide sustained release of curcumin as an active ingredient. Reference is made to the prevention of cardiac events due to the incorporation of a liposomal component into the formulation.
In other embodiments, the compositions for the treatment of neurological autoimmune degenerative diseases (Parkinson's disease, Alzheimer's disease, multiple sclerosis, ALS, sequelae, behavioral and neurological disorders, autistic spectrum disorders, and depression), neoplastic diseases (Cancer) are used.
In certain embodiments, the compositions of the present invention are administered intramuscularly, subcutaneously and / or intra-vascularly.
Certain embodiments include curcumin (diferuloylmethane) encapsulated in a liposomal PLGA envelope, which is referred to as a hybrid nanocurcumin formulation.
In one embodiment, the active ingredient is curcumin, which is a potent natural anticancer agent used in a nanoparticle-based delivery system. One limitation is the QT elongation effect of curcumin, even when associated with nanoparticle-based systems. This makes it difficult to meet FDA requirements for commercial application. The hybrid nanocourate formulation solves this problem and reduces the QT elongation effect of curcumin, making it ideal for commercial application. In addition, the hybrid nanocourate formulation liberates curcumin continuously, which improves systemic availability and reduces the rapid elimination of curcumin in animal models. Therefore, the hybrid nanocourate formulation can be used directly to prepare nanotechnology-based hybrid dosage forms for curcumin. In other embodiments, curcumin may be replaced by various similar drugs or agents. Such compositions may be directly put into production by pharmaceutical companies to be tested in Phase I and Phase II.
Example I: Hybrid Nanocurcumin Formulation: PLGA was dissolved in an organic solvent, acetonitrile, to give a concentration of 10 mg / ml. Curcumin (5%) was dissolved in this phase of polymer and organic solvent. Lipids (DMPC and DMPG) were mixed in different molar ratios and the volume was made up to 1 ml. More details:
Hybrid nanocurcumin formulation: Polymer PLGA (10 mg) was dissolved in 1 ml of organic solvent, acetonitrile, to give a concentration of 10 mg / ml. Curcumin (5% relative to the polymer) was dissolved in this mixture of polymer and organic solvent. Lipids (DMPC and DMPG) were mixed in different molar ratios, and it was found that a DMPC / DMPG ratio = 7.5 / 2.5 gave the best particles. DMPC (Lipid 1) was dissolved in 4% ethanol in water. DMPG (Lipid 2) was dissolved in water and the volume was flow-filled to 1. These solutions were mixed and heated to obtain transparent solutions. The total lipid content relative to the polymer varied from 2 mg to 8 mg. The organic phase was slowly stirred into the aqueous lipid phase, maintaining the ratio of organic to aqueous volume of 1: 1. The emulsion was vortexed for 30 seconds and then sonicated for 5 minutes. Then the whole emulsion system was stirred for 2-3 hours for self-assembly to take place. It was then filtered three times with an Amicon filter (10 kD cutoff). The resulting hybrid particles were snap frozen with liquid nitrogen and lyophilized overnight. Then they were stored at -20 ° C until further use.
The organic phase was slowly stirred into the aqueous lipid phase, maintaining the ratio of organic to aqueous volume of 1: 1. The emulsion was vortexed for 30 seconds and then sonicated for 5 minutes. Then, the entire emulsion system was stirred for 2 hours to allow self-organization to take place. It was then filtered three times with an Amicon filter (10 kD cutoff). The resulting hybrid particles were snap frozen with liquid nitrogen and lyophilized overnight. Then they were stored at -20 ° C until further use.
Characterization of hybrid nanocurcumin: The hybrid nanoparticles were characterized in terms of particle size, drug permeation, encapsulation efficiency, and surface morphology. Figure 4A shows results from a series of studies in which total lipid levels were varied while the molar ratio of two lipids remained constant. In other studies, lipids (DMPC and DMPG) were mixed in different molar ratios, and we found that DMPC / DMPG :: 7.5 / 2.5 gave the best particles. In certain embodiments, the hybrid nanocurcumin is referred to herein as curcumin ER.
Particle Size Distribution: The particle size distribution is shown in Figure 4B. Particle sizes for various batches after lyophilization are listed in Table 1. Particle size analysis of the lyophilized nanoparticles was carried out with a Nanotrac system (Microtrac, Inc., Montgomeryville, PA, USA). The lyophilized nanoparticles were dispersed in double-distilled water and mixed at high speed for 10 seconds on a vortex and then measured in terms of particle size. The results were given as an average of three runs with triplicate measurements per run.
Table 1: Average particle size distribution in all batches
Efficiency of drug loading and encapsulation: The hybrid nanocurcumin was dissolved in acetonitrile and the drug loading and encapsulation efficiency were determined spectrophotometrically. The values are listed in Table 2. Lyophilized hybrid nanoparticles (5 mg) were dissolved in 2 ml acetonitrile to extract curcumin in acetonitrile to determine the encapsulation efficiency. The samples in acetonitrile were gently shaken on a shaker at room temperature for 4 hours to fully extract the curcumin from the nanoparticles into acetonitrile. These solutions were run at 14,000 rpm. (Centrifuge 5415D, Eppendorf AG, Hamburg, Germany) and the supernatant was collected. The suspension (20 μΐ) was dissolved in ethanol (1 ml) and used for the estimates. Curcumin concentrations were measured spectrophotometrically at 450 nm. Under identical conditions, a standard plot of curcumin (0-10 pg / ml) was prepared.
The encapsulation efficiency (EE) of PLGA-CURC was calculated by the following formula:
The percent drug charge was calculated from the total amount of drug extracted from the hybrid nanoparticles, in proportion to the known weight of the nanoparticles.
Table 2: Drug loading and encapsulation efficiency for all lots.
Surface morphology: The surface morphology of the HNC was determined by transmission electron microscopy. The TEM scan is shown below in FIG. The surface morphology of the hybrid nanoparticle was determined by means of transmission electron microscopy (TEM). A small amount of an aqueous solution of the lyophilized hybrid nanoparticles (1 mg / ml) was placed on a TEM grid surface with a filter pad (Whatman No. 1). On the surface of the carbon-coated grid was added a drop of 1% uranyl acetate. After incubation for 1 minute, excess liquid was removed and the grid surface was air-dried at room temperature. Then she was in the
Transmission Electron Microscope (LEO EM910, Carl Zeiss SMT Inc, NY, USA) to which a Gatan SC 1000 CCD camera was attached. HNC are characterized, which involved determination of average particle size, drug loading, and encapsulation efficiency, and the results are shown in FIG.
Evaluation of Hybrid Nanocurcumin: Hybrid nanocurcumin was evaluated by intracellular uptake and MTT assays. As shown in Figure 8, this study revealed a robust uptake of HNC within 1 hour in MiaPaCa pancreatic cancer cells. Intracellular uptake of nanoparticles in pancreatic, prostate and breast cancer cells was determined using a confocal laser scanning microscope (CLSM). For these studies, cells were placed on a coverslip in a 6-well tissue culture plate and incubated at 37 ° C until they were subconfluent. The cells were then exposed to 100 pg / ml concentrations of hybrid nanoparticles labeled with fluorescent Nile red. After incubation for 2 hours, the cells were observed under a microscope. MTT Assay: This assay was performed in the pancreatic cancer cell line MiaPaCa. The IC50 value of the HNC formulation was found to be 22 μΜ concentration (Figure 10). To determine the effect of hybrid nanoparticles on cell growth, a cell vitality assay (MTT assay) was carried out in pancreatic, prostate and breast cancer cell lines. The inhibition of cell growth was measured with the MTT assay. In this assay ~ 200 cells / wells were plated in a 96-well plate and treated with free drug at various μΜ concentrations and equivalent doses of drug-loaded hybrid nanoparticles. The assay was terminated at 48 and 72 hours, and relative growth inhibition was measured compared to control cells. For statistical analysis, all studies were prepared in triplicate and repeated twice. The results were expressed as mean ± standard deviation (S.D.).
Figure 9 shows the results of Western Blot analysis of MiaPaCa cells after treatment with hybrid nanocurcumin (25 μΜ (micromolar)); untreated; Blank value nanoparticles; Curcumin (24h); HNC (24 hours) and; HNC (48 hrs) provided.
Example II:
Assessment of the effects of liposomal PLGA curcumin on the human potassium channel using human embryonic kidney cells (HEK293 cells) transfected with a human hERG gene (human, "a-gogo-related" gene) The example deals with the quantification of the in vitro effects of liposomal PLGA curcumin on the calcium-selective ICR current generated under unstably transfected HEK293 cells under normoxic conditions. The hERG assay is used to assess the potential of a compound to influence the rapidly activating, delayed rectifying potassium channel and is based on the Harmonized Tri-Partite Guidelines " the International Conference on Harmonization (ICH)) [ICHS7a / b] and generally accepted procedures for the testing of pharmaceutical compounds.
General description of the study: Test items: batch A, batch B, batch C, batch D and batch E. Test system: hERG-expressing, transfected HEK293 cell line. Testing carried out: patch-clamp current detection and analysis with whole cells. Test temperature: 35 +/- 2 ° C.
Application of the test articles, positive control and vehicle: 5 min exposure to each concentration in closed circuit perfusion (2 ml / min). 5 minute washout with flow perfusion (2 ml / min) in addition to closed loop perfusion (2 ml / min). The positive control (100 nM E-4031) was given to untreated cells from the same cell line and the same passage for a period of 5 minutes with perfusion in a closed circuit (2 ml / min).
The cells were under continuous stimulation according to the Pulp protocol during the studies, and after 5 minutes exposure to each condition, the cell currents were recorded.
FIG. 11 shows the original data acquisition design.
Detection design when checking the test items or the vehicle: 1 Recording under basic conditions 1 Recording in the presence of the concentration 1, 2 or 31 Recording after washing out (Concentration 3 only) Detection design in the positive control test: 1 Recording under the basic conditions 1 Recording in the presence of the Positive controls = number of reactive, patched cells to which all of the above protocol was applicable.
Statistical analysis: For statistical comparisons, paired Student's t-tests were used. For the test items, the currents recorded after exposure to the various concentrations of the test items were statically compared with the currents recorded under the base conditions. The flows recorded after washout were statistically compared to the flows measured for the highest concentration of test articles. In the same way, currents recorded after the positive control were compared with the currents recorded under basic conditions.
Differences were found to be significant at p ^ 0.05. Exclusion criteria: 1. Non-adherence to drug exposure timeline 2. Instability of seal 3. Patched cell did not generate tail flow 4. No significant effect of positive control 5. More than 10% transient variability Capacity amplitude over the duration of the study.
Impact of the test items on the whole-cell IKr-hERG
streams:
The whole-cell currents generated during a voltage pulse were recorded under basic conditions and after application of the selected concentrations of test objects. Even after a washout period, currents were recorded. The cells were depolarized from the holding potential (-80 mV) to the maximum value of +40 mV for one second, starting at -40 mV and proceeding in steps of 10 mV. Then the membrane potential was repolarized to -55 mV for one second and finally brought back to -80 mV.
The amplitude of the whole cell tail current was measured at a holding potential of -55 mV after activation of the current from -40 to +40 mV. The current amplitude was measured at the maximum (peak) of this tail current. The current density was obtained, in which the current amplitude was divided by the cell capacity measured before the temporary mini¬ mation of the capacitance. According to protocol, from each test object 3, concentrations with respect to the inhibition of the hERG current were analyzed.
The results of the studies demonstrating the analysis of the hERG current density with curcumin, liposomal curcumin and PLGA-curcumin are provided in Figures 6 and 7, which show the analysis of the hERG current density with liposomes + curcumin and liposomes.
Correction for current rundown and solvent effect. All data points presented in this report were corrected for the solvent effect and the time-dependent stream rundown. Current rundown and solvent effects were measured simultaneously by measuring the study design under conditions without a test article (hERG external solution or DMSO) in the same time frame as the test articles. The loss of current amplitude measured in these so-called vehicle models (representing both solvent effects and a time-dependent rundown) was subtracted from the amplitude loss measured in the presence of the test objects to increase the effect of the test articles as a function of the solvent effect and the unavoidable down-time of the current amplitude over time isolate.
These results, as shown in Figures 11-27, quantify the effect of liposomal PLGA curcumin (Lot A, Lot B, Lot C, Lot D and Lot E) on the stably transfected human embryonic under normoxic conditions
Renal cells (HEK293 cells) produced selective current at the rapidly activating, delayed rectifying potassium channel (IKr).
The concentrations of curcumin (6, 12 and 18 μΜ) were selected and reflect a range that is likely to exceed the therapeutic range.
To confirm the reversal effect of the test articles, cells exposed to the highest concentration (18 μΜ) were subjected to a washout period of 5 minutes. The current measured after the washout period did not differ statistically from the current remaining after exposure to the highest concentration of compounds, indicating that the effect of these compounds was not reversible. E-4031 is one of the most selective hERG inhibitors available so far. He was chosen to show the sensitivity of the Prüf¬systems. Three non-pretreated HEK293 hERG cells were exposed to 100 nM E-4031. E-4031 induced a significant inhibition of 81.8% of the current amplitude for 1 + 20.
Information on the samples: Store at -20 ° C and protected from direct sunlight: 1) Lot A -
Total weight of sample - 215 mg curcumin content - 18 pg / mg test sample
Material used - polymer (PLGA), lipid (DMPC + DMPG), curcumin, sucrose. 2) Batch B -
Total weight of sample - 200 mg curcumin content - 6.8 pg / mg test sample
Material used - polymer (PLGA), lipid (DMPC + DMPG), curcumin, sucrose. 3) Lot C -
Total weight of sample - 200 mg curcumin content - 18.2 pg / mg test sample
Material used - polymer (PLGA), chitosan, polyvinyl alcohol (PVA), lipid (DMPC + DMPG), curcumin, sucrose. 4) Batch D - Pure Curcumin Total Weight - 50 mg. 5) Batch E - Liposomal curcumin total volume - 5 ml curcumin content - 6.4 mg / ml
Material Used - Lipid (DMPC + DMPG), Curcumin Molecular Weight Information:
Curcumin molecular weight - 368.38 g / mol PLGA (50:50) - molecular weight - 124 kDa DMPC (PC (14: 0/14: 0)) - molecular weight - 677.933 g / mol DMPG molecular weight - 688.845 g / mol
Sucrose - molecular weight 342.30 g / mol
Chitosan - Low Molecular Weight - 75-85% Deacetylated Polyvinyl Alcohol (PVA) - Average Molecular Weight 30,000- 70,000.
It is contemplated that with respect to each method, kit, reagent or composition of the invention, any embodiment discussed in this specification may be implemented, and vice versa. Compositions of the invention may also be used to carry out the methods of the invention.
Evaluation of the effects of curcumin ER and liposomal curcumin in the mouse lung cancer xenograft model H-460A-549.
The purpose of this study was to quantify the mean tumor volume of the mouse xenograft model during the duration of the treatment. Specifically, encapsulated and liposomally coated curcumin ER and liposomal curcumin were tested on cell lines H-460 and A-549, a lung cancer xenograft model. Briefly described, female 3-4 week old "Hsd: athymic nude mouse Foxnlnu" mice were obtained from Harlan Laboratories, USA. The mice were injected with the cancer cells and the tumor volume was evaluated. Dieliposomal curcumins, curcumin ER and liposomal curcumin were administered once a week by subcutaneous injection of a dose of 20 mg / kg body weight. Figure 28 shows the results of treatment of the breast cancer cell line H-460 in the "Hsd: athymic nude mouse Foxnlnu" mice. Figure 29 shows the results of treatment of breast cancer cell line A-549 in the "Hsd: athymic nude mouse Foxnlnu" mice.
It is understood that certain embodiments described herein are shown by way of illustration only and not as a limitation of the invention. The main features of the present invention can be applied in various embodiments without departing from the scope of the invention. One skilled in the art will recognize many equivalents to the specific methods described herein, or may note such alone through routine experimentation. Such equivalents are intended to be within the scope of the present invention and are covered by the claims.
All publications and patent applications mentioned in the specification reflect the state of the art of a person skilled in the art to which the present invention pertains. All publications and patent applications are incorporated herein by reference, to the same extent as if each particular disclosed publication or patent application were specifically and individually incorporated by reference.
The use of the word "a", "a " or "one " when used in conjunction with the term "containing " in the claims and / or the description, "a "," a " quot or "an ; mean, but can also mean "at least one", "at least one" or "at least one " correspond. The use of the term "or " in the claims, "and / or " unless expressly stated to refer to alternatives, or that the alternatives are mutually exclusive, although the disclosure supports a definition that addresses only alternatives and "and / or"; refers. In this application, the term "about" is used to indicate that a value includes the inherent error variance for the device, the method used to determine the value, or the variation that exists among the study subjects.
As used in the present specification and claims, the words "comprising " (and any form of "comprising", such as "comprise" and "includes"), "have " (and any form of "comprising", such as "pointing to" and "pointing to," "including " (and any form of "including", such as "include" and "includes") or "containing " (and any form of "containing," such as "including" and "containing") are inclusive or undefined and do not exclude additional, non-named elements or process steps.
The term "or combinations thereof" in its present application refers to all permutations and combinations of the elements listed before the term. For example, "A, B, C or combinations thereof" is intended to be " at least one of: A, B, C, AB, AC, BC or ABC and, if the order is important in a particular context, also include BA, CA, CB, CBA, BCA, ACB, BAC or CAB. To stay in this example, expressions are also included which include repeats of at least one element or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB and so on. It will be understood by those skilled in the art that the number of elements or terms in any combination is not typically so limited unless the context dictates otherwise. In certain embodiments, the present invention may also include methods and compositions in which the transition term "consisting essentially of " or "consisting of " can be used.
Any of the compositions and / or methods disclosed and claimed herein may be made and carried out without undue experimentation in light of the present specification. Although the compositions and methods of the present invention have been described as preferred embodiments, it will be apparent to those skilled in the art that variations can be made in the compositions and / or methods and the steps of the method described herein without departing from the scope of the invention To depart from the spirit and scope of the invention.
All such similar substitutes and modifications as would be obvious to a person skilled in the art are intended to be included within the spirit, scope and concept of the invention as defined by the appended claims.

权利要求:
Claims (32)
[1]
A composition for treating cancer comprising: a polymeric nanoparticle core containing at least one polymer and at least one of curcumin or curcuminoids; and at least one layer of at least one lipid on the surface of the polymeric core, wherein the composition does not cause QT prolongation, when an individual is provided with it.
[2]
2. Nanoparticle composition according to claim 1, wherein the at least one polymer comprises at least one of poly (lactic acid-co-glycolic acid) (PLGA), poly (lactic acid), polylactide (PLA) or poly-L-lactide-co-s caprolactone (PLCL).
[3]
The nanoparticle composition according to claim 1, wherein the composition further contains an active ingredient consisting of at least one of an anticancer drug, an antibiotic, a virostat, an antimycotic, an antihelminthic, a nutrient, a small molecule, a siRNA, an antioxidant, and an antibody is selected.
[4]
4. nanoparticle composition according to claim 1, wherein the min¬destens a lipid at least one of 1,2-dimyristoyl-sn-gly-cero-3-phosphocholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), 1,2-Dioctadecanoyl-sn glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino (polyethyleneglycol) (DSPE-PEG), DMPE-PEG-maleimide, lecithin, cholesterol, 1 , 2-Dimyristoyl-sn-glycero-3-phosphoethanola-min-N- (lisamine rhodamine-B-sulfonyl) (ammonium salt) and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- (7-nitro-2 -l, 3-benzoxadiazol-4-yl) (ammonium salt).
[5]
5. Nanoparticle composition according to claim 1, wherein the min¬destens a lipid dimyristoylphosphatidylcholine (DMPC) and di-myristoylphosphatidylglycerol (DMPG) in a molar ratio of 9: 1, 7: 3, 8: 2 or 7.5: 2.5 ,
[6]
6. nanoparticle composition according to claim 1, further comprising at least one targeted feeding means (targeting Mit¬tel), wherein the targeting agent brings the nanoparticles targeted Zuerkrankten tissues / cells, whereby the Ganzkörperdosisminimiert is.
[7]
7. The nanoparticle composition of claim 1, further comprising at least one targeting agent, wherein the targeting agent comprises an antibody or a functional fragment thereof, a small molecule, a peptide, a carbohydrate, an siRNA, a protein, a nucleic acid, an aptamer , a second nanoparticle, a cytokine, a chemokine, a lymphokine, a receptor, a lipid, a lectin, an iron-containing metal, a magnetic particle, a linker, an isotope, or combinations thereof.
[8]
The nanoparticle composition according to claim 1, wherein the nanoparticles have a size of 90 to 150 nm.
[9]
9. nanoparticle composition according to claim 1, wherein a bioavailability of the active ingredient is increased, a QT prolongation redu¬ziert and the active ingredient is released persistently.
[10]
A method of forming a nanoparticle composition, comprising: forming an organic phase by combining at least one polymer, at least one solvent, and at least one of curcumin or curcuminoids; Forming an aqueous lipid phase by mixing at least one lipid with water; Mixing the organic phase with the aqueous lipid phase to form an emulsion; and incubating the emulsion, wherein nanoparticle self-assembly occurs, and wherein the curcumin or curcumin noid nanoparticles do not cause QT prolongation when a subject is provided therewith.
[11]
11. The method of claim 10, wherein the at least one polymer at least one of poly (lactic acid-co-glycolic acid) (PLGA), poly (lactic acid), polylactide (PLA) and poly-L-lactide-co-s-capro lactone (PLCL). ,
[12]
12. The method of claim 10, wherein the organic phase contains PLGA at a concentration of 2-90 mg / ml.
[13]
13. The process according to claim 10, wherein the organic phase contains curcumin in a concentration of 1-15% by weight to volume.
[14]
14. The method of claim 10, wherein the at least one solvent contains an organic solvent which is selected from at least one of acetonitrile, acetone, tert-butyl alcohol, dimethylformamide and hexafluroisopropanol.
[15]
15. The method of claim 10, wherein said at least one lipid comprises at least one of DMPC, DMPG, 1,2-dioctadecanoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-pho-ethanolethanol -N- [amino (polyethylene glycol) (DSPE-PEG), DMPE-PEG-maleimide, lecithin, cholesterol, 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- (lisamine-rhodamine-B-sulfonyl) (ammonium salt) and 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- (7-nitro-2-1,3-benzoxadiazol-4-yl) (ammonium salt).
[16]
16. The method of claim 10, wherein the at least one lipid comprises DMPC and DMPG in a molar ratio of 9: 1, 7: 3, 8: 2 or 7.5: 2.5.
[17]
17. The method of claim 10, wherein mixing the organic phase with the aqueous lipid phase comprises at least one of slowly stirring the organic phase into the aqueous lipid phase, mixing the organic phase with the aqueous lipid phase on the vortex mixer, or mixing the orga and the aqueous phase with the aqueous lipid phase.
[18]
18. The method of claim 10, wherein incubating the emulsion for 2 hours stirring the emulsion.
[19]
19. The method of claim 10, further comprising at least one of the following: (1) separating the nanoparticles after incubating the emulsion; (2) filtering the nanoparticles after incubating the emulsion; (3) freezing the nanoparticles; (4) lyophilizing the nanoparticles; or (5) attaching a targeting agent to the nanoparticles.
[20]
The method of claim 10, further comprising attaching at least one targeting agent, wherein the targeting agent selectively targets the nanoparticle to diseased tissues / cells, thereby minimizing the whole-body dose.
[21]
21. The method of claim 10, further comprising attaching at least one targeting agent to the nanoparticles, wherein the targeting agent contains an antibody or functional fragment thereof capable of recognizing a target antigen.
[22]
22. The method of claim 10, wherein the nanoparticles have a size of 90 to 150 nm.
[23]
23. A method of treating a patient suspected of having a disease, comprising administering nanoparticles, the nanoparticles containing a polymeric core comprising at least one polymer and at least one active agent and at least one layer of at least one lipid on the surface of the polymeric core, wherein the active ingredient is suspected of causing QT prolongation when provided to an individual.
[24]
The method of claim 23, wherein administering nanoparticles comprises administering the nanoparticle by intramuscular, subcutaneous, intravascular or intravenous administration.
[25]
The method of claim 23, wherein the disease is selected from the group consisting of neurological, oncological and metabolic diseases.
[26]
26. The method of claim 23, wherein the disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, multiple sclerosis, ALS, a sequelae, behavioral and cognitive disorders, a disease of the autistic spectrum, depression and neoplastic disease.
[27]
27. The method of claim 23, wherein the active ingredient is sustained release.
[28]
28. A method of forming a nanoparticle composition that prevents the active ingredient from causing QT prolongation, comprising: forming an organic phase by combining at least one of a polymer, at least one solvent, and the agent causing QT prolongation; Forming an aqueous lipid phase by mixing at least one lipid with water; Mixing the organic phase with the aqueous lipid phase to form an emulsion; and incubating the emulsion, whereby self-assembly of nanoparticles occurs.
[29]
A pharmaceutical composition comprising: a nanoparticle for drug delivery comprising a polymer, a drug which causes QT prolongation, and at least one layer of at least one lipid encapsulating the polymer and the drug, said agent not causing QT prolongation gently.
[30]
30. A method of treating a patient suspected of having a disease, said method comprising administering nanoparticles, said nanoparticles containing a polymeric core comprising at least one polymer, curcumin, and at least one layer of at least one lipid on the surface of said polymeric core wherein treating the patient does not cause QT prolongation.
[31]
31. A method of treating an individual suspected of having cancer, comprising: identifying that a patient is believed to have cancer; and providing the subject with an amount of at least one of curcumin or curcuminoids in an amount sufficient to reduce the cancer in the subject, the at least one of curcumin or curcuminoids residing in a polymeric nanoparticle core containing at least one polymer and at least one of curcumin or curcuminoids; and at least one layer of at least one lipid on the surface of the polymeric core, wherein the at least one of the curcumin or curcuminoid nanoparticles does not cause QT prolongation when provided to an individual.
[32]
32. The method of claim 31, wherein the cancer is a pancreatic, prostate or breast cancer.

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法律状态:
2018-02-15| REJ| Rejection|Effective date: 20180215 |

优先权:

申请号 | 申请日 | 专利标题

US201261695827P| true| 2012-08-31|2012-08-31|

US14/016,056|US9138411B2|2012-08-31|2013-08-31|Curcumin-ER, a liposomal-PLGA sustained release nanocurcumin for minimizing QT prolongation for cancer therapy|

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