Abstract:
Curcumin has shown anti-inflammatory and anti-angiogenic properties that could be useful in treating various diseases such as those of rheumatology and oncology. However, curcumin is very poorly absorbed and has a very low bioavailability. This patent describes a method of increasing the delivery of curcumin by complexing it with cyclodextrins. Cyclodextrins are well known in the food industry and have been used to carry other drugs to increase bioavailability. The new combination of cyclodextrins and curcumin has been tested in pre-clinical inflammation models where it has demonstrated efficacy superior to both the positive control and curcumin.

Description:
[0001]    This application is based on U.S. Provisional Patent No. 61/135,443 Application filed Jun. 22, 2009, the entire contents of which are incorporated herein. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to method of use patent for the complex of curcumin and cyclodextrin to treat diseases affecting various systems, in humans and animals. The diseases include neurological diseases such as Alzheimers, autoimmune or inflammatory or allergic diseases such as asthma and rheumatoid arthritis, oncologic diseases, respiratory system diseases such as chronic obstructive lung disease, dermatologic diseases, cardiovascular diseases such as hyperlipidemia and coronary artery disease, gastrointestinal, hepatic and pancreatic diseases such as inflammatory bowel disease, metabolic diseases such as diabetes, urologic, and infectious diseases, and for wound healing. Administration can be oral, topical, parenteral, nasal, inhalational, or suppository. 
       BACKGROUND OF THE INVENTION 
       [0003]    Turmeric and turmeric extracts have long been active ingredients in compositions for oral and topical application to treat diseases and conditions. 
         [0004]      Curcuma longa  (Fam. Zingiberaccae), or turmeric, is a spicy plant that is a common ingredient in curry powder. Turmeric has a strong yellow color that is useful in providing a pleasing color to foods such as prepared mustard. Turmeric has antimicrobial properties that can help preserve food and prevent spoilage. 
         [0005]    Turmeric is one of the oldest herbs in Ayurveda materia medica, and has been used in Ayurveda medicine internally as a tonic, to settle an upset stomach, and as a blood purifier. Turmeric has been applied topically to wounds to stop bleeding, speed healing and reduce scaring. Ground turmeric has been used as a topical salve, particularly in India, to prevent and treat a variety of skin diseases and conditions. 
         [0006]    The significance of turmeric in medicine has changed in modern times with the scientific observation of turmeric&#39;s therapeutic properties. The same ground dried rhizome of  Curcuma longa , which has been used for centuries as a spice, food preservative and coloring agent, has been found to be a rich source of beneficial phenolic compounds, turmerin peptide, and curcuminoids. Curcuminoids have scientifically documented anti-oxidant, anti-inflammatory, anti-bacterial, anti-fungal, antiparasitic, anti-mutagen, anti-cancer and detoxification properties. Curcuminoids are recognized for their broad biological activity and safety of use. Significant data are available on the safety, toxicity, dose range, pharmacokinetics, and other biological properties of turmeric and its components, including curcuminoids and turmerin peptide. Turmeric components are well tolerated while providing anti-oxidant benefits, inhibit microbial growth, inhibit several enzymes, and inhibit abnormal cell growth in studies of cells, animals, and humans. 
         [0007]    Studies have shown that turmeric components can inhibit enzymes associated with disease states. Extensive in vitro and in vivo testing has shown that turmeric inhibits chemically-induced epidermal ornithine decarboxylase activity, epidermal DNA synthesis, and the promotion of skin tumors in mice (Conney, A. H. et al., Adv. Enzyme Regul., 31:385-396, 1991; Huang, M. T. et al., Cancer Res., 48:5941-5945, 1988; Lu, Y. P. et al., Carcinogenesis, 14:293-297, 1993; Azuine, M. A., Bhide, S. V., Nutr Cancer, 17:77-83, 1992). Further studies suggest that turmeric also reduces arachidonic acid-induced rat paw and mouse skin edema and markedly inhibits epidermal lipoxygenase and cyclooxygenase activity in vitro (Rao, T. S. et al., Indian J. Med. Res., 75:574-578, 1982; Conney, A. H. et al., Adv. Enzyme Regul., 31:385-396, 1991; Huang, M. T. et al., Cancer Res., 48:5941-5945, 1988). Phosphorylation events can also be influenced by curcumin, as it has been reported that curcuminoids inhibit protein kinase C activity induced by 12-O-tetradecanoyl-phorbol-13-acetate in NIH 3T3 cells (Liu, J. Y., Lin, S. J., and Lin, J. K., Carcinogenesis, 14:857-861). 
         [0008]    Turmeric can fight against microbial infections and parasitic infestations. In humans, ingestion of turmeric has been used to treat biliary infections where it demonstrates bacteriostatic or bacteriocidal effects against organisms involved in cholecystitis (Ramprasad, C. et al., Ind. J. Phys. and Pharm., 1:136-143, 1957; Lutumski, J. et al., Planta Med., 26:9-19, 1974). Topical application of a turmeric paste for the treatment of scabies has also shown good results (Charles, V., Charles, S. X., Trop. Geogr. Med., 44:178-181, 1992). 
         [0009]    Their potential use of turmeric and turmeric extracts in the prevention of cancer and in the treatment of infection with human immunodeficiency virus (HIV) are the subject of intensive laboratory and clinical research. It has been shown that curcuminoids decreased p24 antigen production in acutely or chronically infected cells with HIV-1, a paradigm of anti-viral activity (Li, C. J. et al., Proc. Natl. Acad. Sci. USA, 90:1839-1842, 1993). The addition of turmeric to the diet has been shown to inhibit azoxymethanol-induced colonic epithelial cell proliferation and focal areas of dysplasia (Huang, M. T. et al., Cancer Letters, 64:117-121, 1992). It has also been shown to interfere with the formation of covalent carcinogen-DNA adducts (Mukudan, M. A. et al., Cardnogenesis, 14:493-496, 1993). 
         [0010]    Fat metabolism is likewise influenced by curcumin. It can render bile non-lithogenic in mice (Hussain, M. S. et al., Indian J. Med. Rcs., 96:288-291, 1992). Curcuminoids can reduce the production of PMA-induced lipid peroxidation and 8-OH-deoxyguanosine formation in mouse fibroblast cells (Shih, C. A., and Lin, J. K., Carcinogenesis, 14:709-712, 1993). Oral administration of curcuminoids in human volunteers has been shown to significantly decrease the level of serum lipid peroxides (33%), increase HDL cholesterol (29%), and decrease total serum cholesterol (11.63%) (Soni, K. B, Kuttan R., Indian J. Phys. Pharmacol., 36:273-275, 1992). 
         [0011]    Curcumin can moderate the immune system as well as smooth muscle cell proliferation. Activation responses to phytohemagglutinin and mixed lymphocyte reaction were reduced in human peripheral blood mononuclear cells in the presence of curcuminoids. Furthermore, curcuminoids inhibited the proliferation of rabbit vascular smooth muscle cells stimulated by fetal calf serum. Curcuminoids had a greater inhibitory effect on platelet derived growth factor-stimulated proliferation than on serum-stimulated proliferation (Huang, H. C. et al., Eur. J. Pharmacol., 221:381-384, 1992). 
         [0012]    The anti-inflammatory properties of curcuminoids were shown to inhibit the 5-lipoxygenase activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets (Ammon, H. P. T. et al, J. Ethopharmacol., 38:113-119, 1993). Curcuminoids had no significant effect on quercetin-induced nuclear DNA damage, lipid peroxidation and protein degradation, and thus has the unique potential of acting as both pro- and antioxidants, depending on the redox state of their biological environment (Saura, C. et al., Cancer Letters, 63:237-241, 1992). Administration of curcuminoids in mice exhibited antioxidant properties by significantly reducing the scavenging of peroxides and other activated oxygen species, (Soudamini, K. K. et al., Indian J. Phys. Pharmacol. 36:239-243, 1992). 
         [0013]    Pathogenesis of diseases like Alzheimer&#39;s show mounting evidence of oxidative damage and inflammatory factors. Unfortunately, despite strong epidemiology and rationale, antioxidant and NSAED approaches to these age-related diseases have generally not been successful in the clinic. For example, vitamin E has failed in trials for Alzheimer&#39;s and heart disease prevention, while COX inhibitors have failed for Alzheimer treatment and been dropped for prevention efforts with traditional antioxidants (selenium, vitamin E, β carotene), estrogens, and COX-2 inhibitors. The demographics of aging population drive an urgent need for suitable alternatives for prevention and possible treatment of one or more of the chronic diseases of aging. 
         [0014]    As a tumeric extract, curcumin is the yellow in yellow curries and is used as a food additive, for example, in yellow mustard. Like the “wonder drug” aspirin, which remains one of our few successful preventive agents, the long-term health potential of curcumin has a substantial history and a relatively well-established scientific basis. It has been identified as a major bioactive agent in an empirically developed system of traditional Indian medicine. 
         [0015]    Curcumin (diferulomethane) is not only a potent natural antioxidant and anti-inflammatory agent, acting on NFkB and AP-I regulated pro-inflammatory mediators including COX-2, iNOS, il-1 and TNFα, but has multiple useful activities and has shown therapeutic potential in many pre-clinical in-vitro and animal models for diseases, often related to aging. These include cancers (colon, prostate, breast, skin, leukemia, etc.) (Agarwal et al., 2003), prion disease (Caughey et al., 2003), atherosclerosis (Miguel et al., 2002; Ramaswami et al., 2004), stroke (G. Sun, personal comm.), CNS alcohol toxicity (Rajakrishnan et al., 1999), traumatic brain injury (F. Gomez-Pinilla, UCLA personal comm.), Huntington&#39;s disease (MF Chesselet, personal comm.), Marie-Charcot Tooth (J. Lupski, personal comm.), multiple sclerosis (EAE), and Alzheimer&#39;s disease. 
         [0016]    Curcumin can block aggregation of Aβ and other amyloid-forming peptides to toxic fibrils and oligomers; chelate metals that cause lipid and protein and DNA oxidative damage to the brain; inhibit aberrant inflammation through AP-I and NFkB transcription; stimulate beneficial microglial phagocytosis like the amylid vaccine to clear amyloid out of brain; and inhibit production of BACE under conditions of oxidative damage and inflammation, thus limiting Aβ production. Broad Spectrum efficacy for age-related disease is accentuated by positive life extension data (Kitani et al., 2004). Based on its outstanding safety profile and efficacy in multiple disease models with oxidative damage and inflammatory factors, curcumin has shown excellent potential for disease pathogenesis in Alzheimer models. Curcumin is on the short list of useful agents for cancer chemoprevention under development by the National Cancer Institute (NCI), which put curcumin through the National Toxicology Program and pre-clinical safety and efficacy trials (KelJoff et al., 1996; Chainani-Wu, 2003). Curcumin has passed several phase II trials for cancer and is currently in further clinical trials for cancers at multiple sites in the US and abroad (MD Anderson web site). 
         [0017]    Curcumin&#39;s structure resembles that of amyloid binding compounds. Amyloid dyes like Congo Red (CR) are known to bind via planar hydrophobic groups with appropriately spaced charge, and to suppress β-amyloid and other β-sheet-dependent peptide aggregation and toxicity. The Congo Red analogue, Chrysamine G, is more brain permeant and retains CR&#39;s amyloid binding properties. Curcumin shares the 19 angstrom CR spacing between its polar phenol groups; is readily brain permeant; and binds amyloid peptides, inhibiting their aggregation and toxicity in vitro. Curcumin effectively reduces amyloid accumulation in vivo in APP Tg mice. Because CR&#39;s anti-amyloid binding is generic and potentially relevant to other β-sheet intraneuronal aggregates including Huntington, a-synuclein, prions and tau, curcumin&#39;s anti-amyloid activity may be relevant beyond extracellular amyloid to intraneuronal aggregates. In fact, curcumin is one of the most effective anti-prion compounds ever tested in vitro, although it did not work in vivo with oral dosing of unstated formulation (Caughey et al., 2003). This raises the limitations of curcumin oral bioavailability, the subject of the present invention. The benefits of curcumin as a treatment for multiple diseases with aggregating amyloid proteins and other CAG repeat disorders are being established, and its efficacy in treating stroke, head trauma, metabolic syndrome, and many other conditions, including some forms of cancer and arthritis, as well as in promoting wound healing, is also beginning to be understood. All of these therapeutic applications are limited, however, because of poor intestinal absorption. 
         [0018]    Nuclear factor-.kappa B (NFkB) is very important to cell function and is critical to the immune system and cancer biology. Agents that can suppress the activation of nuclear factor kappa B (NFkB) and activator protein-1 (AP-1), may be able to block tumorigenesis and inflammation. Curcumin blocks tumor necrosis factor (TNF) induced activation of NFkB in a concentration and time dependent manner. The effects are not cell type specific because it blocked TNF induced NFkB activation in a variety of cells. The NFkB-dependent reporter gene transcription activated by TNF was also suppressed. 
         [0019]    Rel/NFkB transcription factors are a family of structurally related eukaryotic transcription factors that are involved in the control of a large number of normal cellular processes, such as immune and inflammatory responses, developmental processes, cellular growth, and apoptosis. In addition, these factors are active in a number of disease states, including cancer, arthritis, chronic inflammation, asthma, neurodegenerative, and heart disease. Rel/NFkB transcription factors include a collection of proteins conserved from the fruit fly  Drosophila melanogaster  to humans. Among the commonly used model organisms, these transcription factors are notably absent in yeast and the nematode  Caenorhabditis elegans . In part this may be because one of the primary roles of these factors is to control a variety of physiological aspects of immune and inflammatory responses. A pathway similar to the Rel/NFkB signaling pathway may also control certain defense responses in plants. 
         [0020]    In most cells NFkB is present as a latent, inactive, I kappa B bound complex in the cytoplasm. When a cell receives any of a multitude of extracellular signals, NFkB rapidly dissociates from 1 kappa B, enters the nucleus and activates gene expression. Therefore a key step for controlling NFkB activity is the regulation of the interaction of I kappa B and NFkB. Many of the molecular details of this control mechanism are now understood. Almost all of the signals that lead to the activation of NFkB converge on a high molecular weight complex that contains a serine specific I kappa B kinase (IKK). IKK is an unusual kinase in that in most cells IKK contains at least three distinct subunits: IKK alpha, IKK beta and IKK gamma. IKK alpha and IKK beta are related catalytic kinase subunits, and IKK gamma is a regulatory subunit that serves as a control mechanism for the catalytic subunits. In the classical or canonical pathway, activation of IKK complex leads to the phosphorylation by IKK beta. of two specific serines near the N terminus of IkB, which targets IkB for ubiquitination and degradation by the proteasome. In the non-canonical pathway, the p100-RelB complex is activated by IKK alpha mediated phosphorylation of the C-terminal region of p100, which leads to degradation of the p100 IkB-like C-terminal sequences to generate p52-RelB. In either pathway, the unmasked Rel/NFkB complex can then enter the nucleus to activate target gene expression. In the canonical pathway, one of the target genes activated by NFkB is that which encodes I kappa B. Newly synthesized I kappa B can enter the nucleus, remove NFkB from DNA, and export the complex back to the cytoplasm to restore the original latent state. Thus, the activation of the NFkB pathway is generally a transient process, lasting from 30 to 60 minutes in most cells. 
         [0021]    In some normal cells, such as B cells, some T cells, Sertoli cells and some neurons, NFkB is constitutively located in the nucleus. In addition, in many cancer cells, including breast cancer, colon cancer, prostate cancer, lymphoid cancers, and probably many others, NFkB is constitutively active and located in the nucleus. In some cancers, this is due to chronic stimulation of the IKK pathway, while in other cells, such as some Hodgkin&#39;s and diffuse large B-cell lymphoma cells, the gene encoding IkB is sometimes mutated and defective. Moreover, several human lymphoid cancer cells have mutations or amplifications of genes encoding Rel/NFkB transcription factors, which may enable them to accumulate in or rapidly and repeatedly cycle through the nucleus. It is thought that continuous nuclear Rel/NFkB activity protects cancer cells from apoptosis and in some cases stimulates their growth. Therefore, many current anti-tumor therapies seek to block NFkB activity as a means for inhibiting tumor growth or sensitizing the tumor cells to more conventional therapies, such as chemotherapy. 
         [0022]    Diseases Associated with NFkB: 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
               
               
                 Disease 
                 Reference 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 Aging 
                 Reuter et al., 2003 
               
               
                 3 
                 Cardiac Hypertrophy 
                 Purcell &amp; Molkentin, 2003 
               
               
                 4 
                 Muscular Dystrophy (type 2A) 
                 Baghdiguian et al., 1999 
               
               
                 5 
                 Catabolic disorder 
                 Holmes-McNary, 2002 
               
               
                 6 
                 Diabetes, Type 1 
                 Ho &amp; Bray, 1999 
               
               
                 7 
                 Diabetes, Type 2 
                 Yuan et al., 2001 
               
               
                 8 
                 Hypercholesterolemia 
                 Wilson et al., 2000 
               
               
                 9 
                 Atherosclerosis 
                 Ross et al., 2001 
               
               
                 10 
                 Heart Disease 
                 Valen et al., 2001 
               
               
                 11 
                 Ischemia/reperfusion 
                 Toledo-Pereyra &amp; Lopez- 
               
               
                   
                   
                 Neblina, 2002 
               
               
                 12 
                 Angina Pectoris 
                 Ritchie, 1998 
               
               
                 13 
                 Pulmonary Disease 
                 Christman et al., 2000 
               
               
                 14 
                 Acid-induced Lung Inury 
                 Madjdpour et al., 2003 
               
               
                 15 
                 Renal Disease 
                 Guijarro &amp; Egido, 2001 
               
               
                 16 
                 Leptospiriosis renal disease 
                 Yang et al., 2001 
               
               
                 17 
                 Gut Diseases 
                 Neurath et al., 1998 
               
               
                 18 
                 Skin Diseases 
                 Bell et al., 2003 
               
               
                 19 
                 Incontinentia pigmenti 
                 Courtois &amp; Israel A, 2000 
               
               
                 20 
                 Asthma 
                 Pahl &amp; Szelenyi, 2002 
               
               
                 21 
                 Arthritis 
                 Roshak et al., 2002 
               
               
                 22 
                 Crohns Disease 
                 Pena &amp; Penate, 2002 
               
               
                 23 
                 Ocular Allergy 
                 Bielory et al., 2003 
               
               
                 24 
                 Appendicitis 
                 Pennington et al., 2000 
               
               
                 25 
                 Pancreatitis 
                 Weber &amp; Adler, 2001 
               
               
                 26 
                 Periodonitis 
                 Nichols et al., 2001 
               
               
                 27 
                 Inflammatory Bowel Disease 
                 Dijkstra et al., 2002 
               
               
                 28 
                 Sepsis 
                 Wratten et al., 2001, 
               
               
                   
                   
                 Abraham, 2003 
               
               
                 29 
                 Silica-induced 
                 Chen &amp; Shi, 2002 
               
               
                 30 
                 AIDS (HIV-1) 
                 Hiscott et al., 2001 
               
               
                 31 
                 Autoimmunity 
                 Hayashi &amp; Faustman, 2000 
               
               
                 32 
                 Lupus 
                 Kammer &amp; Tsokos, 2002 
               
               
                 33 
                 Neuropathological Diseases 
                 Cechetto, 2001, Mattson &amp; 
               
               
                   
                   
                 Camandola, 2001 
               
               
                 34 
                 Sleep apnoea 
                 Lavie, 2003 
               
               
                 35 
                 Alzheimers Disease 
                 Mattson &amp; Camandola, 2001 
               
               
                   
               
             
          
         
       
     
         [0023]    Constitutive Activation of NFkB in Human Cancer Cells 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                   
               
               
                 Cancer Type 
                 Reference 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 Breast 
                 Nakshatri et al., 1997; Sovak et al., 
               
               
                   
                   
                 1997 
               
               
                 2 
                 Cervix 
                 Nair et al., 2003 
               
               
                 3 
                 Ovary 
                 Dejardin et al., 1999; Huang et al., 2000 
               
               
                 4 
                 Vulva 
                 Seppanen &amp; Vihko, 2000 
               
               
                 5 
                 Prostate 
                 Huang et al., 2001b; Palayoor et al., 
               
               
                   
                   
                 1999 
               
               
                 6 
                 Kidney 
                 Oya et al., 2001 
               
               
                 7 
                 Liver 
                 Tai et al., 2000 
               
               
                 8 
                 Pancreas 
                 Wang et al., 1999; Sclabas et al., 2003 
               
               
                 9 
                 Esophygeal/gastric 
                 Sutter et al., 2004 
               
               
                 10 
                 Stomach 
                 Sasaki et al., 2001 
               
               
                 11 
                 Colon 
                 Lind et al., 2001 
               
               
                 12 
                 Thyroid 
                 Visconti et al., 1997 
               
               
                 13 
                 Melanoma 
                 Yang &amp; Richmond, 2001 
               
               
                 14 
                 Head and neck 
                 Ondrey et al., 1999 
               
               
                 15 
                 Cylindromatosis 
                 Kovalenko et al., 2003; Brummelkamp 
               
               
                   
                   
                 et al., 2003; Tropmpouki et al., 2003 
               
               
                 16 
                 Oral carcinoma 
                 Nakayama et al., 2001 
               
               
                 17 
                 Astrocytoma/glioblastoma 
                 Hayahsi et al., 2001 
               
               
                 18 
                 Neuroblastoma 
                 Bian et al., 2002 
               
               
                 19 
                 Acute lymphoblastic leukemia 
                 Kordes et al., 2000 
               
               
                 20 
                 Acute myelogenous leukemia 
                 Guzman et al., 2001 
               
               
                 21 
                 Acute T-cell leukemia 
                 Arima &amp; Tei, 2001 (HTLV-1) 
               
               
                 22 
                 Chronic lymphocytic leukemia 
                 Furman et al., 2000 
               
               
                 23 
                 Burkitts Lymphoma (EBV) 
                 Knecht et al., 2001 
               
               
                 24 
                 Mantle cell lymphoma 
                 Martinez et al., 2003 
               
               
                 25 
                 Multiple myeloma 
                 Berenson et al., 2001 
               
               
                 26 
                 Diffuse large B-cell lymphoma 
                 Davis et al., 2001; Shaffer et al., 2002 
               
               
                 27 
                 Hodgkin&#39;s lymphoma 
                 Bargou et al., 1996, 1997; Staudt, 2001 
               
               
                   
               
             
          
         
       
     
         [0024]    Due to its action on NFkB and its anti-oxidative properties, in addition to its many other effects, curcumin has been proposed to treat various diseases mentioned in [0016] and [0017]. Although many groups have come up with theoretical ideas for improving absorption of curcumin, most have involved entirely in vitro studies, probably because of the difficulty in measuring curcumin and its metabolites in tissue. 
         [0025]    Although curcumin is an effective medication in multiple animal models for human diseases when given with food at high doses (typically 2,000-5,000 ppm in diet in cancer trials), the current dogma is that it is so poorly bioavailable that it cannot be used for treatment outside the colon in humans. Curcumin is very hydrophobic and typically is not dissolved when delivered as a powder extract in common nutraceuticals. Most curcumin activities require 100-2,000 nanomolar (0.1-2 micromolar) levels in vitro, but current supplements result in negligible, low nanomolar blood levels (see Sharma et al., 2004). R. Sharma&#39;s group at Leicester has tried repeatedly and been unable to achieve significant blood levels beyond the low nanomolar range (Garcea G., Jones J D, Singh R., Dennison A R, Farmer P B, Sharma R A, Steward W P, Gescher A J, Berry D P Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br J. Cancer. 2004 Mar. 8; 90 (5): 1011-5. PMBD: 14997198.) They and others conclude that delivery of effective concentrations of oral curcumin to systemic tissues (outside the GI tract) is “probably not feasible.” Most of the literature supports this view, leading the NCI to focus on colon cancer. In addition, curcumin has very poor bioavailability, with T max  of only 3-5 minutes 
         [0026]    Curcumin has been extensively studied in various diseases ranging from phase Ito phase IIb. In Phase-I clinical studies, oral administration of curcumin is well tolerated at pharmacological concentration. However, as mentioned above, its bioavailability is very poor. Cheng et al conducted a phase I study in patients with Bowens Disease and found that doses up to 8000 mg/day for 3 months were well tolerated (Cheng, A L, et al Anticancer Res 2001. 21, 2895-2900). Serum concentrations peaked at 1-2 hours and then gradually declined. Maximum serum concentrations ranged from 0.5+/−0.11 mM at 4000 mg/day to 1.77+/−1.87 mM at 8000 mg/day. No difference was observed with repeated dosing (on day 30). Many other phase I and phase II studies have come to similar conclusions—that while there is a lot of scientific merit to the use of curcumin, its poor bioavailability limits its use (reviewed by Hatcher H et al, 2008). 
         [0027]    Three factors limit curcumin absorption and need to be addressed: 1) rapid glucuronidation/sulfation of curcumin&#39;s phenolic hydroxyl groups and high “first pass” clearance; 2) curcumin is unstable in aqueous solution at pH 7 and above; and 3) curcumin is very hydrophobic and typically is not water soluble at acidic pH and when delivered as a dry powder in existing supplements. (Most of the curcumin is never absorbed and simply passes through the GI tract and is excreted.) 
         [0028]    Solubilization is critical to prevent this, but curcumin requires pH 8.5 to dissolve completely. For this reason, cancer patients take huge doses, typically up to 8 gms a day. Diarrhea is a common side-effect. Garcea, G. et al. (2004) report that with patients taking 3.6 gms of curcumin a day (as a standard powder extract capsule supplied by Sabinsa Corporation), blood and liver levels achieved are negligible. They conclude that “the results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.” 
         [0029]    Curcumin is not soluble at acidic pH and breaks down when solubilized and diluted into water at neutral or alkaline pH (e.g., in the GI tract, after the small intestine), due to keto-enol transformations in the β-diketonebridge. In addition, curcumin is susceptible to rapid sulfation/glucuronidation. The major U.S. supplier, Sabinsa, has tried to make a more bioavailable form by adding Bioperine (pipeline) to inhibit glucuronidation. Such an approach is flawed, however, because most glucuronidation takes place in the upper GI tract, where the pH is acidic, and curcumin is not completely dissolved until pH 8.5 and higher. Even worse, inhibiting glucuronidation can cause serious health risks. Glucuronidation is protective against many toxins and involved in the metabolism of commonly used drugs. Most elderly patients are on multiple drugs, at levels likely to be unsafely altered by inhibition of glucuronidation. 
         [0030]    Cyclodextrins are cyclic oligomers of glucose; these compounds form inclusion complexes with any drug whose molecule can fit into the lipophile-seeking cavities of the cyclodextrin molecule. They make an excellent vehicle for carrying other molecules, especially insoluble compounds such as curcumin. 
         [0031]    Cyclodextrin can be a-, β-, or gamma-cyclodextrin. Some of the cycldextrins are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of (3-cyclodextrin, carboxyamidomethyl-β-cyclodextrin, carboxymethyl-p-cyclodextrin, hydroxypropyl-β-cyclodextrin and diethylamino-β-cyclodextrin. In the composition according to this invention hydroxy-p-cyclodextrin is preferred but others can be used. The substituted-cyclodextrins may also be suitable, including hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of y-cyclodextrin. 
         [0032]    Alpha-cyclodextrin contains six glucopyranose units; beta-cyclodextrin contains seven glucopyranose units, and gamma cyclodextrin contains eight glucopyranose units. The molecules are believed to form a truncated cone having a core opening of 4.7-5. 3 A, 6.0-6. 5 A and 7.5-8. 3 A in alpha, beta, or gamma cyclodextrin respectively. The composition according to this invention may comprise a mixture of two or more of the alpha, beta, or gamma cyclodextrins. Usually, however the composition according to this invention will comprise only one of the cyclodextrins. 
         [0033]    There are several patents that indicate that complexes of cyclodextrin with drug substances improve the side effect profile of the drug substance. Szejtli et al., U.S. Pat. No. 4,228,160, disclosed that the frequency and severity of gastric and duodenal erosion and ulceration in rats caused by indomethecin is improved in an oral formulation of a complex of beta-cyclodextrin and indomethacin in a 2:1 ratio, but is not improved and in fact worsens in the same oral formulation of a complex of beta-cyclodextrin and indomethacin in a 1:1 ratio. 
         [0034]    Shimazu et al., U.S. Pat. No. 4,352,793, discloses that a formulation wherein bencyclane fumarate, an anti-convulsive compound with beta.-cyclodextrin or gamma.-cyclodextrin yields a complex in which the bencyclane fumarate is an inclusion compound. These complexes, when formulated as a liquid suitable for oral administration were claimed to be less irritating in an isotonic buffered pH 7 solution when administered as drops to the eyes of rabbits, as compared to bencyclane fumarate drops at the same drug concentration in an inactive vehicle. Shimazu et al., also disclosed that similar complexes dissolved in rabbit blood in-vitro yielded reduced hemolysis as compared to equal concentrations of bencyclane fumarate alone mixed with rabbit blood. 
         [0035]    Masuda et al., U.S. Pat. No. 4,478,811, disclose ophthalmic formulations of beta or gamma-cyclodextrin complexes of the nonsteroidal anti-inflammatory compound fluorobiphenylacetic acid that are less irritating and painful than the same formulations of fluorobiphenyl acetic acid alone. Uekama et al., U.S. Pat. No. 4,565,807, disclose complexes of alpha, beta, and gamma cyclodextrin, piprofen and a pharmaceutically acceptable base. Piprofen is an analgesic and anti-inflammatory compound, which is bitter and can cause irritation to the gastrointestinal tract. The complexes disclosed in the patent have improved less bitter taste and are less irritating to the gastrointestinal tract than is the uncomplexed compound piprofen. No preparations suitable for intravenous injection were disclosed. 
         [0036]    Lipari, U.S. Pat. No. 4,383,992, disclose topical and ophthalmic solutions comprising a number of different steroid-related compounds including corticosteroids, androgens, anabolic steroids, estrogens, and progestagens complexed with beta cyclodextrin. None of the cyclodextrin compounds disclosed by Lipari are substituted or amorphous cyclodextrins. In addition, none or the steroid related compounds disclosed by Lipari are 5 beta steroids. 
         [0037]    Pitha et al., U.S. Pat. No. 4,596,795 disclose complexes containing amorphous hydroxypropyl-beta cyclodextrin and sex hormones, particularly testosterone, progesterone and estradiol as lyophilized powders. These tableted complexes are disclosed as appropriate for administration sublingually or buccally with absorption occurring across the corresponding mucosal membrane. None is administered in solution parenterally. In addition none of the steroid related compounds disclosed by Pitha are 5 beta steroids. 
         [0038]    Pitha et al., U.S. Pat. No. 4,727,064, disclose complexes containing water soluble amorphous substituted cyclodextrin mixtures and drugs with substantially low water solubility which may be lyophilized and the lyophilized powder formed into dosage forms suitable for absorption trans-mucosally across the oral, buccal or rectal mucosa. The solutions of amorphous, water soluble cyclodextrin alone and not in a complex with a drug substance are disclosed as nonirritating topically, and having low toxicity, both systemic and local, when applied parenterally. These solutions of substituted cyclodextrin alone were tested and shown to be non-lethal when substantial amounts of the cyclodextrin solution were administered intra-peritoneally in mice. A number of categories of drugs are disclosed in Pitha for complex with cyclodextrin derivatives and include inter alia vitamins, salts of retinoic acid, spironolactone, antiviral agents, diuretics, anticoagulants, anticonvulsant and anti-inflammatory agents. Significantly, Pitha, while disclosing that aqueous solutions of 50% cyclodextrin may be used for the purpose of determining solubility of drugs in such solutions does not indicate that such solutions are suitable for intravenous administration. No attempt is made to qualify the solution as to its pyrogenicity. The claimed compositions of matter in the reference contain only cyclodextrin and drug. Liquid or semi-liquid compositions of matter, which are claimed in the reference, appear to be made of cyclodextrins with higher degrees of substitution with hydroxypropyl groups. These cyclodextrins are themselves semi-solid or liquids according to the reference. Thus no aqueous formulations of water, cyclodextrin and drug are disclosed or claimed as suitable for parenteral administration in the reference. 
         [0039]    Bekers et al. (1989) describe the investigation of stabilization of mitomycin-C and several related mitomycins by formation of a complex with cyclodextrin. The authors indicate that at the pH ranges studied alpha and beta cyclodextrin as well as heptakis-(2,6,-di-O-methyl)-beta cyclodextrin and dimethyl beta cyclodextrin, have no influence on stabilization of mitomycin-C pH dependant degradation. Gamma Cyclodextrin is reported as having measurable stabilizing effect on mitomycin in acidic media at pH&#39;s above 1. 
         [0040]    Bodor, U.S. Pat. No. 5,024,998, and Bodor, U.S. Pat. No. 4,983,586, disclose a series of compositions comprising complexes of hydroxypropyl-beta cyclodextrin (HPCD) complexed to a difficult to solubilize drug, and HPCD complexed to a drug which has first been complexed to a specific class of drug carriers characterized as redox drug carriers. The complex of drug and redox carrier is itself difficult to solubilize and is highly lipophilic due to the presence of pyridine derivatives as part of the redox carrier complex. Bodor U.S. Pat. No. 5,024,998 and U.S. Pat. No. 4,983,586 further claim that a solution of 20 to 50% hydroxypropyl beta cyclodextrin and lipophilic drug-redox carrier complex, or 20 to 50% hydroxypropyl beta cyclodextrin and lipophilic and/or water labile drug is useful in a method of decreasing the incidence of precipitation of a lipophilic and/or water labile drug occurring at or near the injection site and/or in the lungs or other organs following parenteral administration. Significantly the Bodor references attribute the precipitation and organ deposition problems associated with parenteral administration of lipophilic drugs to the effects of organic solvents used to solubilize the drug in the parenteral vehicle. The Bodor references additionally state that drugs which are particularly useful in the parenteral composition and methods disclosed therein are those which are relatively insoluble in water but whose water solubility can be substantially improved by formulation with 20 to 50% of the selected cyclodextrin, e.g. HPCD, in water. Thus it is quite clear that the Bodor references are directed to prevention of the phenomenon of precipitation of insoluble drugs and insoluble drug-carrier complexes. 
         [0041]    U.S. Pat. No. 5,824,668 discloses the composition of 5 beta steroid with cyclodextrin suitable for parenteral administration for treating various diseases. 
         [0042]    Muller et al. (1992) described the complex formation of digitoxin with beta and gamma cyclodextrins. Uekama et al. (1983) described the inclusion complexes of the digitalis glycosides digitoxin, digoxin, and methyl digoxin with three cyclodextrins, the alpha, beta, and gamma homologues in water and in the solid state. Solid complexes in a molar ratio of 1:4 of the digitalis glycosides with gamma cyclodextrin were prepared and their in-vivo absorption examined. The rapidly dissolving form of the gamma cyclodextrin complex significantly increased plasma levels of digoxin (approximately 5.4-fold) after oral administration to dogs. Ueda et al. (1999) examined the complex formation of digitoxin with delta cyclodextrin and observed enhanced solubility. Okada and Koizumi (1998) studied the complex formation of digitoxin and digoxin with modified beta cyclodextrins. 
         [0043]    U.S. Pat. No. 6,407,079 discloses the pharmaceutical compositions comprising inclusion compounds of sparingly water-soluble or water labile drugs with beta cyclodextrin ethers or beta cyclodextrin esters and the process for the preparation of such compositions. The patent claims cardiac glycosides as one of the types drugs for the treatment of cardiac disorders. The patent further states that molar ratio of the drug to the cyclodextrin derivative is from about 1:6 to 4:1. The patent claims injectable formulations with 0.45 micron filtering and sterilization. According to the patent document, the patent was filed in 1988 and was awarded in 2002. However, the complexation of digitoxin and digoxin with beta and gamma cyclodextrins was disclosed to the public by the inventors in 1992 (Muller et al. 1992). 
         [0044]    The following is a list of approved drugs using cyclodextrins in combination: 
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
           
               
                   
               
               
                 Cyclodextrin/Drug 
                   
                   
               
               
                 Region 
                 Administration 
                 Trade name 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Alprostadil (PGE 1 ) 
                 Intravenous 
                 Prostavastin, 
                 Europe, 
               
               
                   
                   
                 Caverject, Edex 
                 Japan, 
               
               
                   
                   
                   
                 United 
               
               
                   
                   
                   
                 States 
               
               
                 Cefotiam hexetil HCl 
                 Oral 
                 Pansporin T 
                 Japan 
               
               
                 Limaprost 
                 Oral 
                 Opalmon, Prorenal 
               
             
          
           
               
                 -Cyclodextrin 
               
             
          
           
               
                 Benexate 
                 Oral 
                 Ulgut, Lonmiel 
                 Japan 
               
               
                 Dexamethasone 
                 Dermal 
                 Glymesason 
                 Japan 
               
               
                 Iodine 
                 Topical 
                 Mena-Gargle 
                 Japan 
               
               
                 Nicotine 
                 Sublingual 
                 Nicorette 
                 Europe 
               
               
                 Nimesulide 
                 Oral 
                 Nimedex, Mesulid 
                 Europe 
               
               
                 Nitroglycerin 
                 Sublingual 
                 Nitropen 
                 Japan 
               
               
                 Omeprazole 
                 Oral 
                 Omebeta 
                 Europe 
               
               
                 Dinoprostone (PGE 2 ) 
                 Sublingual 
                 Prostarmon E 
                 Japan 
               
               
                 Piroxicam 
                 Oral 
                 Brexin 
                 Europe 
               
               
                 Tiaprofenic acid 
                 Oral 
                 Surgamyl 
                 Europe 
               
             
          
           
               
                 2-Hydroxypropyl--cyclodextrin 
               
             
          
           
               
                 Cisapride 
                 Rectal 
                 Propulsid 
                 Europe 
               
               
                 Hydrocortisone 
                 Buccal 
                 Dexocort 
                 Europe 
               
               
                 Indomethacin 
                 Eye drops 
                 Indocid 
                 Europe 
               
               
                 Itraconazole 
                 Oral, I.V 
                 Sporanox 
                 Europe, 
               
               
                   
                   
                   
                 United 
               
               
                   
                   
                   
                 States 
               
               
                 Mitomycin 
                 Intravenous 
                 Mitozytrex 
                 United 
               
               
                   
                   
                   
                 States 
               
             
          
           
               
                 Randomly methylated -cyclodextrin 
               
             
          
           
               
                 17-Oestradiol 
                 Nasal spray 
                 Aerodiol 
                 Europe 
               
               
                 Chloramphenicol 
                 Eye drops 
                 Clorocil 
                 Europe 
               
             
          
           
               
                 Sulphobutylether -cyclodextrin 
               
             
          
           
               
                 Voriconazole 
                 Intravenous 
                 Vfend 
                 Europe, 
               
               
                   
                   
                   
                 United 
               
               
                   
                   
                   
                 States 
               
               
                 Ziprasidone maleate 
                 Intramuscular 
                 Geodon, Zeldox 
                 Europe, 
               
               
                   
                   
                   
                 United 
               
               
                   
                   
                   
                 States 
               
             
          
           
               
                 2-Hydroxypropyl--cyclodextrin 
               
             
          
           
               
                 Diclofenac sodium 
                 Eye drops 
                 Voltaren 
                 Europe 
               
               
                   
               
             
          
         
       
     
       SUMMARY OF THE INVENTION 
       [0045]    The present invention describes curcumin cyclodextrin complexes that exhibit enhanced bioavailability of curcumin and can be used as therapeutic agents to treat, and possibly slow or prevent a number of diseases and conditions. The composition can be provided as a gel, capsule, tablet, powder, liquid, or other pharmaceutically acceptable form. 
         [0046]    The invention also provides a method of use for treating, slowing, and/or preventing diseases. The diseases include neurological diseases such as Alzheimers, autoimmune or inflammatory or allergic diseases such as asthma and rheumatoid arthritis, oncologic diseases, respiratory system diseases such as chronic obstructive lung disease, dermatologic diseases, cardiovascular diseases such as hyperlipidemia and coronary artery disease, metabolic diseases such as diabetes, gastrointestinal, hepatic and pancreatic diseases such as inflammatory bowel disease, urologic, and infectious diseases and for wound healing. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0047]    Cyclodextrin may be purchased from a number of vendors including Sigma-Aldrich, Inc. (St. Louis, Mo., USA). In addition, other forms of amorphous cyclodextrin having different degrees of substitution or glucose residue number are available commercially. A method for the production of hydroxypropyl-p-cyclodextrin is disclosed in Pitha et al., U.S. Pat. No. 4,727,064 which is incorporated herein by reference. 
         [0048]    To produce the formulations according to the invention, a pre-weighed amount of cyclodextrin, which is substantially pyrogen free is placed in a suitable depyrogenated sterile container. Methods for depyrogenation of containers and closure components are well known to those skilled in the art and are fully described in the United States Pharmacopeia 23 (United States Pharmacopeial Convention, Rockville, Md. USA). Generally, depyrogenation is accomplished by exposing the objects to be depyrogenated to temperatures above 400° C. for a period of time sufficient to fully incinerate any organic matter. As measured in U.S. P. Bacterial Endotoxin Units, the formulation will contain no more than 10 Bacterial Endotoxin Units per gram of amorphous cyclodextrin. By substantially pyrogen free is meant that the hydroxypropyl-p-cyclodextrin contains less than 10 U.S.P. bacterial endotoxin units per gram using the U.S.P. method. Preferably, the hydroxypropyl-(3-cyclodextrin will contain between 0.1 and 5 U.S.P. bacterial endotoxin units per mg, under conditions specified in the United States Pharmacopeia 23. 
         [0049]    Make a 20% HPβ-cyclodextrin solution, pH 11-12: Place 2 g HPβ-cyclodextrin (Sigma/Aldrich #332593) per 8 ml water in a stoppered graduated cylinder with at least a 50% volume reserve; shake vigorously to dissolve, then place in an ultrasonic bath briefly to clarify; vortex to ensure homogeneous mixing. Add a stir bar and 10% NaOH dropwise with stirring until pH is between 11 &amp; 12; qs to 2 g of cyclodextrin/10 ml water and re-mix by vortexing. Use at room temperature. 
         [0050]    Make a 15 mg/ml curcumin stock solution, pH 11-12: Suspend 15 mg of curcumin (Sigma C7727) per 0.9 ml of an ethanol/water (10/90) mix in a beaker (with a stir bar) that is large enough for a pH monitoring electrode. Add 10% NaOH dropwise while stirring and using a pipette to wet any remaining powder with liquid until the drug is well suspended and suspension turns red/purple. Insert pH electrode and continue adding NaOH until pH is between 11 and 12 and suspended drug is dissolved (clear purple). Then qs to 15 mg/1.0 ml and stir for ˜5 more minutes to make sure drug is in solution. Then add to cyclodextrin solution immediately (see 0052 below) as alkaline curcumin is unstable. 
         [0051]    Make neutral 3 mg/ml Cyclodextrin: Curcumin (CDC) dosing solution: Add 2 ml of alkaline curcumin stock per 8 ml of alkaline cyclodextrin in a beaker with stir bar; curcumin should stay dissolved. Then complex the curcumin with the cyclodextrin by slowly lowering the pH via dropwise addition of 0.8 M citric acid with stirring and pH monitoring until pH is between 6 &amp; 7. As pH drops the color will change to a clear orange/yellow. 
         [0052]    Store drug in dark or amber vials. Use immediately or store in the refrigerator; the drug is still clear after overnight refrigeration. 
         [0053]    The drug can be dried in a speed vac and stored at room temperature. Reconstitution can be achieved by mixing with water to the original concentration. 
         [0054]    Efficacy: The efficacy of CDC was compared to native curcumin in a mouse paw edema model.
       Purpose: To compare the oral efficacy of an aqueous curcumin suspension (C) with that of a curcumin cyclodextrin complex (CDC) in the mouse carrageenan paw inflammation model   Materials: Curcumin (C) (Sigma C7727, lot #096K1092); HPβ-Cyclodextrin (CD) (Sigma/Aldrich 332593, lot #04806CJ); Indomethacin (Sigma 18280, lot #098K1500); λCarrageenan (Fluka 22049, lot #1408463); ketamine (Bioniche Pharma NDC 67457-001-10); xylazine (Lloyd Labs, lot #LA33806); calipers (Fisher 15-077-957); ethanol (E) (Decon Labs #2716, lot #A01190801 L).   Animals: 35 male CD-1 mice, 20-30 g (Harlan)   Experimental Design/Methods/Groups:
           1. Acclimatize the mice for 3+ days after receipt. Weigh mice within 24 hrs of dosing to calculate dosing volume. Remove food 2 hours before dosing; restore food ˜2 hours after dosing.   2. Vehicle and Drugs:
               Vehicle: Make 20 ml of 20% cyclodextrin (CD) by dissolving 4 g CD/20 ml sterile water. Make 10 ml of Ethanol/water (25%/75%) by mixing 2.5 ml of Ethanol and 7.5 ml sterile water. Make 5 ml of Ethanol/water (5%/95%). Separate CD into two 10 ml aliquots; add 10% NaOH dropwise to one of them until the pH is 11-12; adjust the other to pH 6-8 if needed. For the vehicle group, make 5 ml of vehicle by mixing 1 ml of Ethanol/Water (25%/75%) with 4 ml of 20% CD, pH 6-8. Store in fridge for up to 3 days.   Curcumin: Make 5 ml of 3 mg/ml curcumin dosing suspension by suspending 15 mg of drug in 5 ml of Ethanol/Water (5%/95%); vortex and sonicate to make a fine suspension. Check ability to push through an appropriately sized gavage needle; if clumpy, homogenize and re-check. Store in fridge overnight protected from light.   CDC: Make 5 ml of 15 mg/ml curcumin stock by suspending 75 mg in 5 ml of Ethanol/Water (25%/75%). Then add 10% NaOH dropwise with stirring until pH reaches 11-12 and drug is dissolved; stir 10 mins (solution will be red/purple). Then make 10 ml of dosing solution by taking 2 ml of dissolved drug and adding slowly to 8 ml of pH 11-12 20% CD solution with constant stirring; mix for 10 mins. Next complex the curcumin by slow dropwise addition of 0.8 M citric acid until pH is 6-7 and solution is clear yellow. Store in fridge overnight protected from light.   Indomethacin: Make 10 ml of dosing solution by suspending 5 mg in 10 ml of sterile water with stirring, then adding 0.1 N NaCO3 dropwise until solid disappears and pH is 7-8. Store in fridge for up to 1 week.   
               3. Carrageenan: Make 2 ml of 1% carrageenan by dissolving 20 mg in 2 ml of saline at 4° C. and then vortexing, warming and sonicating. Test for injection resistance by 27G and 28 G needles. Store in refrigerator overnight.   4. Groups: See Group Variables table below.   
               
 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
           
               
                   
               
               
                 Group Variables 
               
             
          
           
               
                   
                   
                   
                   
                 Dose 
                 Dose 
                 Dose 
               
               
                 Group 
                 No. of 
                 Test 
                 Dose 
                 Level 
                 Volume 
                 Conc. 
               
               
                 No. 
                 Animals 
                 Article 
                 Route 
                 (mg/kg) 
                 (mL/kg) 
                 (mg/mL) 
               
               
                   
               
               
                 1 
                 8 
                 Vehicle 
                 p.o. 
                 N/A 
                 10 
                 N/A 
               
               
                 2 
                 8 
                 Curcumin 
                 p.o. 
                 30 
                 10 
                 3 
               
               
                 3 
                 8 
                 CDC 
                 p.o. 
                 30 
                 10 
                 3 
               
               
                 4 
                 8 
                 Indometha 
                 p.o. 
                 5 
                 10 
                 0.5 
               
               
                   
               
             
          
         
       
       
         
           
             
               
                 5. Procedure: Measure thickness of each paw of each mouse. 
               
             
           
         
       
     
         [0068]    Dose mice p.o. 30 minutes before carrageenan injection. Anesthetize with ketamine/xylazine (100/12 mg/kg, i.p.) 15 minutes before carrageenan injection. At t=0, inject left footpad of each mouse with 25 μL of 1% carrageenan, using a 27 or 28 G needle. At 3 hours, measure thicknesses of each paw with calipers, holding mouse vertical and paw out with forceps. Calculate edema by subtracting right paw thickness from left paw thickness. 
         [0069]    Results: The paw was measured at 3 hours after oral gavage of curcumin (30 mg/kg), Indomethacin (5 mg/kg), and CDC (30 mg/kg) to mice. After 3 hours, the swelling was 0.59 mm for CDC, 0.66 mm for curcumin, 0.73 mm for indomethacin, and 0.78 mm for vehicle control. The difference between CDC and curcumin/indomethacin was statistically significant, with p&lt;0.05. 
         [0070]    The invention has been described with reference to various embodiments and examples, but is not limited thereto. Variations may be made without departing from the invention&#39;s scope, which is limited only by the appended claims and equivalents thereof. 
       REFERENCES 
     Curcumin 
       [0000]    
       
         Yang F et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem, Vol. 280, No. 7. (18 Feb. 2005), pp. 5892-5901. 
         Hatcher H, Planalpb R, Chob J, Tortia,d F M, and Tortic,d S V. Curcumin: From ancient medicine to current clinical trials. Cell. Mol. Life Sci. 65 (2008) 1631-1652. 
         Aggarwal B B, Kumar A, Bharti A C. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003 January-February; 23(1A):363-98. 
         Cheng, A L, Hsu, C H, Lin, J K, Hsu, M M, Ho, Y F, Shen, T S, Ko, J Y, Lin, J T, Lin, B R, Ming-Shiang, W, Yu, H S, Jee, S H, Chen, G S, Chen, T M, Chen, C, Lai, M K, Pu, Y S, Pan, M H, Wang, Y J, Tsai, C C and, Hsieh, C Y. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001. 21, 2895-2900. 
         Hatcher H, Planalp R, Cho J, Torti F M and Torti S V. Curcumin: From ancient medicine to current clinical trials. Cell. Mol. Life Sci. 65 (2008) 1631-1652 
       
     
         [0076]    Drug delivery and complexes (including cyclodextrins)
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         [0099]    NFkB
   Abraham E (2003) Nuclear factor-kB and its role in sepsis-associated organ failure. Journal of Infectious Diseases 187: S364-S369   Aradhya S and Nelson D L (2001) NF-kB signaling and human disease. Current Opinions in Genetics and Development 11: 300-306.   Arima N and Tei C (2001) HTLV-I Tax related dysfunction of cell cycle regulators and oncogenesis of adult T cell leukemia. Leukemia and Lymphoma 40: 267-278   Baghdiguian S, Martin M, Richard I, Pons F, Astier C, Bourg N, Hay R T, Chemaly R, Halaby G, Loiselet J, Anderson L V, Lopez de Munain A, Fardeau M, Mangeat P, Beckmann J S and Lefranc G (1999) Calpain 3 deficiency is associated with myonuclear apoptosis and profound perturbation of the IkB alpha/NF-kB pathway in limb-girdle muscular dystrophy type 2A [published erratum appears in Nat Med July 1999; 5(7):849]. Nature Medicine 5: 503-511   Baldwin A S Jr (2001) Series introduction: the transcription factor NF-kB and human disease. Journal of Clinical Investigation 107: 3-6   Bargou R C, Leng C, Krappmann D, Emmerich F, Mapara M Y, Bommert K, Royer H-D, Scheidereit C and Dorken (1996) High-level nuclear NF-kB and October-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. Blood 87: 4340-4347   Bargou R C, Emmerich F, Krappmann D, Bommert K, Mapara M Y, Arnold W, Royer H D, Grinstein E, Greiner A, Scheidereit C and Dorkin B (1997) Constitutive NF-kB-RelA activation is required for proliferation and survival of Hodgkin&#39;s disease tumor cells. Journal of Clinical Investigation 100: 2961-2969   Barnes P J (2002) New treatments for COPD. Nature Reviews Drug Discovery 1: 437-446   Baumann B, Weber C K, Troppmair J, Whiteside S, Israel A, Rapp U R and Wirth T (2000) Raf induces NF-kB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Proceedings of the National Academy of Sciences USA 97: 4615-4620   Bell S, Degitz K, Quirling M, Jilg N, Page S and Brand K (2003) Involvement of NF-kB signalling in skin physiology and disease. Cell Signal 15:1-7   Berenson J R, Ma H M and Vescio R (2001) The role of nuclear factor-kB in the biology and treatment of multiple myeloma. Seminars in Oncology 28: 626-633   Besancon F, Atfi A, Gespach C, Cayre Y E and Bourgeade M F (1998) Evidence for a role of NF-kB in the survival of hematopoietic cells mediated by interleukin-3 and the oncogenic TEL/platelet-derived growth factor beta fusion protein. Proceedings of the National Academy of Sciences USA 95: 8081-8086   Bian X, Opipari Jr A W, Ratanaproeksa A B, Boltano A E, Lucas P C and Castle V P (2002) Constitutively active NF-kB is required for the survival of S-type neuroblastoma. Journal of Biological Chemistry 277: 42144-42150   Bielory L, Kempuraj D and Theoharides T (2003) Topical immunopharmacology of ocular allergies. 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