FIELD OF THE INVENTION

The present invention relates to inflammation and pain treatment. More specifically, synergistic compositions for alleviating or preventing inflammatory mediated disorders in mammals and various forms of degenerative musculoskeletal diseases resulting therefrom, such as rheumatoid arthritis and osteoarthritis. The present invention further relates to compositions exhibiting the synergistic activity of mediating inflammation through the simultaneous effect of the COX2, CB2 and TPRV1 pathways. Particularly, the compositions comprise complexed curcuminoids and complexed cannabidiol optionally containing other ingredients, which shows a synergistic anti inflammatory and antioxidant property.

BACKGROUND OF THE INVENTION

Inflammatory diseases affect more than fifty million Americans. As a result of basic research in molecular and cellular immunology over the last ten to fifteen years, approaches to diagnosing, treating and preventing these immunologically based diseases has been dramatically altered. One example of this is the discovery of an inducible form of the cyclooxygenase enzyme. Constitutive cyclooxygenase (COX), first purified in 1976 and cloned in 1988, functions in the synthesis of prostaglandins (PGs) from arachidonic acid (AA). Three years after its purification, an inducible enzyme with COX activity was identified and given the name COX-2, while constitutive COX was termed COX 1. COX-2 gene expression is under the control of pro-inflammatory cytokines and growth factors. Thus, the inference is that COX-2 functions in both inflammation and control of cell growth. While COX-2 is inducible in many tissues, it is present constitutively in the brain and spinal cord, where it may function in nerve transmission for pain and fever. The two isoforms of COX are nearly identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. On the other hand, PGs synthesized by

COX-2 in immune cells are central to the inflammatory process. The discovery of COX-2 has made possible the design of new drugs and synergistic compositions that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1.

A yellow pigmented fraction isolated from the rhizomes of Curcuma longa contains curcuminoids belonging to the cinnamoyl methane group. Curcuminoids are present to the extent of 3 to 5 percent in the raw material. They are considered the most important active ingredients and are believed to be responsible for the biological activity of Curcuma longa. Though their major activity is anti-inflammatory, curcuminoids have been reported to possess antioxidant, antiallergic, wound healing, antispasmodic, antibacterial, antifungal, antitumor and antiHIV activity as well. Curcumin was isolated in 1815 and structurally defined in 1910. Other major curcuminoids isolated from Curcuma longa include demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids may be found in other botanicals in addition to Curcuma longa. Such as Curcuma xanthorrhiza and Curcuma Zedoaria. Curcuminoids are well known for their anti inflammatory activity. Turmeric is one of the oldest anti-inflammatory drugs used in Ayurvedic medicine. The pharmacokinetics involving the safety, toxicity, dose range and biological properties of turmeric and its components, including curcumin is known, and the turmeric is readily available in various food stores. Curcumin is not highly bioavailable orally. The anti-inflammatory properties of curcumin 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 ah, J. Etho 40 pharmacoL, 1993,38, 113-119).

Phytocannabinoids regulate inflammatory responses through effects upon cytokine production. Cannabinoid type 2 receptor activation was shown to reduce the production of MCP-2 chemokine in vitro cell models. Cannabidiol elevates anandamide and inhibits MCP-2 IL6 and IL8 through both CB2 and TPRV 1 signaling (Petrosino S et al J Pharmacol Exp Ther 2018) Cannabidiol is a nonpsychoactive cannabinoid isolated from the hemp plant. Cannabidiol has low water solubility and very low oral

bioavailability, being both poorly absorbed in the gastrointestinal tract due to its poor solubility and heavily metabolized in the over during first pass metabolism. Therefore, novel complexes of cannabidiol offer enhanced absorption and effect compared to the parent compound. Although cannabidiol is a weak CB2 agonist its CB2 agonist activity may be synergistically enhanced through combination with one of the naturally occurring terpenes also found in hemp notably beta-caryophyllene. Beta-caryophyllene is a highly volatile terpene compound found in hemp and therefore it must also be complexed to provide processing stability and higher bioavailability. The combination of complexed cannabidiol and beta-caryophyllene provide enhanced activation of the CB2 pathway as well as TPRV 1 activation.

A composition of complexed curcuminoids and complexed cannabidiol with beta- caryophyllene, and optionally other ingredients for reducing or preventing inflammation of joint tissues, for treating arthritis or other inflammatory conditions and reducing pain therein has not yet been discovered. A composition comprising complexed curcuminoids, complexed cannabidiol with beta-caryophyllene and optionally other ingredients to synergistically inhibit COX-2, and activate

CB2 and TPRV 1 receptors with high specificity and reduce joint inflammation has also not yet been discovered. An important need, therefore, exists for dietary composition suitable for mammalian patients that are synergistic in that they have stronger effects than the sum of the effects of the individual components and also synergistic with standard clinical treatment of inflammatory conditions. In the prior art, there are no such synergistic anti-inflammatory compositions for inflammatory diseases as described herein. It is, therefore, an objective of the present invention to provide a safe dietary supplement composition, which reduces or prevents inflammation and pain in 5- lipoxygenase mediated disorders like inflammatory diseases (e.g. rheumatoid arthritis and osteoarthritis). Such a composition, containing complexed curcuminoids and complexed CBD with beta-caryophyllene, would be useful for preserving the health of joint tissues, for treating arthritis or other inflammatory conditions and reducing pain therein. U.S. Pat. No. 6,521,271 described the methods of promoting the improvement of skin condition by administering a turmeric component and glycolic acid to a patient afflicted with a skin disorder. U.S. Pat. No. 6,264,995 described an herbal composition for reducing inflammation in bones and joints by inhibiting the enzyme cyclooxygenase-2. U>S. Patent 8420132B2 described the combination of curcuminoids and boswellic acid for relieving inflammation and antioxidant scavenging in various diseases such as cancer and inflammatory bowel disease.

This composition is prepared from tetrahydrocurcumin and other hydrogenated curcumins that are complexed with beta-cyclodextrin, from hemp extracted cannabidiol with beta-caryophyllene that is complexed with beta-cyclodextrin. These complexes can then be incorporated into a liposomal matrix and dried either as powders or as thin oral dispersible strips for buccal or sublingual delivery to the mammalian patient. The compositions can further comprise other anti-inflammatory polyphenols as are known, other CB2 agonists as are known and other TPRV 1 agonists as are known. U.S. Pat. No. 6,841,177 disclosed antiproliferative and photosensitization activities of Curcuma longa extract and its use in proliferative diseases Such as psoriasis, as reducers of plasmatic fibrinogen and the Apolipoprotein B/Apollipopro tein A-I quotient, without altering other coagulation parameters. U.S. Pat. No. 6,440,468 disclosed a method for obtaining apolar and polar extracts of Curcuma and applications thereof. A process for obtaining the apolar extract comprises: (a) extracting the rhizomes with an organic solvent; (b) filtration and evaporation to dryness of the extract; (c) dissolution of the oleoresin obtained in hot conditions, precipitation while allowing to cool down and filtration of the solid; (d) drying and recrystallizing the Solid in order to obtain a product having a purity in curcuminoids higher than

90%. A process for obtaining the polar extract comprises (i) extraction of the rhizomes with water at 50-70° C. and (ii) filtration 10 15 25 30 35 40 45 50 55 60 65 4 and evaporation of the water. Application of the compositions and preparations as catchers of free radicals and anti-aging agents, as well as reducing agents to reduce the plasma levels of lipid peroxides in human beings are disclosed. U.S. Pat. No. 5,494,668 disclosed a method of treating degenerative musculoskeletal diseases Such as rheumatoid arthritis and osteoarthritis in an animal, typically a human, comprises administering to the animal, typically in a convenient dosage form, a therapeutically effective amount of the beneficiated extracts of the plants ashwagandha (Withania somnifera), Sallaiguggul (Boswellia serrata), turmeric (Curcuma longa), and ginger (Zingiber officinale) in a predetermined proportion relative to each other with or

without other biologically active inorganic ingredients, such as Zinc sulfate. The beneficiated plant extracts are made in accordance with a novel process which is also disclosed.

US Patent Application 20030152585A1 disclosed an herbal composition comprising a mixture of herbs such as Tinospora cordifolia, Aloe Vera, Curcuma loraga, Withania Somnifera, Achyranthus asperea, Ocinum sanctum and Picorrhiza Kur roa for treatment of hematological malignancies. U.S. Pat. No. 6,979,470 disclosed curcuminoid compositions comprising an effective amount of a curcuminoid species and an effective amount of a diterpene lactone species, a triterpene species or derivatives thereof that have a synergistic effect on specific inhibition of inducible COX-2 activity and have minimal effect on COX-1 activity. US Patent Application 20040247700A1 disclosed curcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase-2 and this composition is useful for treating e.g. inflammation or arthritis, comprising curcuminoid and diterpene lactone or triterpene, and specifically inhibits inducible cyclooxygenase-2 (COX-2) activity. US Patent Application

20030096027A1 and 20050129791A1 disclosed curcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase. It is also disclosed this composition for treating e.g. inflammation or inflammation-based diseases, comprising curcuminoid species and alpha-acid (hops plant products) or beta-acid (lupulones).

US Patent Application 20030108628A1 described curcuminoid compositions, which exhibits synergistic inhibition of the expression and/or activity of cyclooxygenase. It also disclosed this composition for treating e.g. inflammation or arthritis, comprising curcuminoid and diterpene Intone or triterpene, and specifically inhibits inducible cyclooxygenase-2 (COX-2) activity. US Patent Application 20050191375A1 described synergistic anti-inflammatory pharmaceutical compositions and related methods using curcuminoids or methylxanthines. It also disclosed the composition for reducing inflammation or treating e.g. pain, cancer, rheumatoid arthritis, psoriasis, ulcerative colitis, and conjunctivitis comprises fraction isolated or derived from hops and methylxanthine. US Patent Application 20050123632A1 described the anti-inflammatory activity of a specific turmeric extract. It also disclosed a mixture of turmeric oils for pharmaceutical or nutraceutical composition for treating inflammation e.g. rheumatoid arthritis, comprises hexane Soluble fraction. US Patent Application 20030216600A1 described novel polyhydroxy curcumins having antioxidant activity and these new polyhydroxy curcumins are useful as antioxidants. European Patent 1133992A1 described novel pharmacological activities of Curcuma longa extracts. The use of an aqueous alcoholic extract of Curcuma longa in a composition having e.g.

photosensitizing, antiproliferative and fibrinogen level reducing activity, used e.g. for treating psoriasis is also disclosed. The patent W003007975A1 described curcuminoid compositions, which exhibits synergistic inhibition of the expression and/or activity of cyclooxygenase-2. It also disclosed the composition useful for treating e.g. inflammation or arthritis, comprising curcuminoid and diterpene lactone or triterpene, and specifically inhibits inducible cyclooxygenase-2 (COX 2) activity. The patent W006062681A1 described curcuminoid compositions exhibiting synergistic inhibition of the expression and/or activity of cyclooxygenase-2. The formulation comprises, as a first component an effective amount of a curcuminoid species and an effective amount of a second component being from the group consisting of an alpha-acid species (hops plant products) or beta-acid species (lupulones) or derivatives thereof. The patent

W005084230A2 described synergistic anti-inflammatory pharmaceutical compositions and related methods using curcuminoids or methylxanthines. The composition useful for reducing inflammation or treating e.g. pain, cancer, rheumatoid arthritis, psoriasis, ulcerative colitis, and conjunctivitis comprises fraction isolated or derived from hops and methylxanthine is disclosed. The patent GB2388539A1 disclosed two polyherbal formulations for treating cancer, comprises a mixture of six or four herbs, or a mixture of active ingredients extracted or synthesized from herbs. The first formulation comprises a mixture of Glycine max, Lycopersicon esculentum, Allium sativum, Curcuma longa, Linum usitatissimum, and Convolvulus arvensis. The second formulation comprises a mixture of Tinospora cordifolia, Withania somnifera, Phyllanthus, and Asparagus racemosus. U.S. Pat. No. 5,629,351 described boswellic acid compositions and preparation thereof. The composition comprises a new fraction containing known boswellic acids and new 2-alpha, 3-alpha-dihydroxy- urs-12-en-24-oic acid is useful as a synergistic anti-inflammatory, antiarthritic and antiulcerogenic agent. The patent AU0075253A5 described novel pharmacological activities of Curcuma longa extracts. The use of an aqueous alcoholic extract of Curcuma longa in a composition having e.g. photosensitizing, antiproliferative and fibrinogen level reducing activity, used e.g. for treating psoriasis is also disclosed.

Thus, none of the prior art mentioned above relates to a composition comprising complexed curcuminoids combined with complexed cannabidiol/ beta-caryophyllene combinations. It is, therefore, an object of the present invention to provide a safe dietary supplement composition, which alleviates or prevents COX-2 mediated disorders, inflammatory diseases like rheumatoid arthritis, through a synergistic effect of COX 2 inhibition and CB2 and TPRV 1 agonism.

DETAIL DESCRIPTIONS OF THE INVENTION

The present invention provides a novel synergistic dietary supplement

composition for alleviating COX 2 mediated mammalian disorders. The present invention provides a dietary synergistic mixture of cyclodextrin complexed curcuminoids, specifically hydrogenated curcuminoids, along with at least a complexed mixture of cannabidiol and beta-caryophyllene. Preferably these complexes are cyclodextrin complexes and most preferably these cyclodextrin complexed cannabidiol and beta caryophyllene are contained within a desiccated liposomal matrix. These liposomal matrices can be in powdered form or in the form of oral thin dispersible films for buccal or sublingual delivery of actives. The present invention further provides a dietary synergistic mixture of complexed hydrogenated curcuminoids, and complexed cannabidiol and beta-caryophyllene combination and optionally containing one or more of glucosamine, resVeratrol, garlic extract, chondroitin, bromelain, boswellic acid and quercetin, other anti-inflammatory polyphenols and other CB2 agonists. The present invention further provides for these complexes to preferably be in a desiccated liposomal matrix. These compositions may be administered buccally, sublingually, orally, or rectally across the mucosa through powders, gums, troches, lozenges, thin orally fast dissolving strips and other methods as known in the art.

The resulting compositions of the above invention synergistically both reduce inflammation and pain in a mammalian subject.

Although the invention has been explained in relation to its preferred

embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the invention.