Use of anabolic agents, anti-catabolic agents, antioxidant agents, and analgesics for protection, treatment and repair of connective tissues in humans and animals

Abstract

The present invention relates to compositions for the modulation of inflammation in connective tissues in humans and animals and the modulation of markers of such inflammation, including COX-2, TNF-α, IL-1β, iNOS, p38, and chemokines, comprising any or all of anabolic, anti-catabolic, anti-oxidant and analgesic agents, including aminosugars, S-adenosylmethionine, arachadonic acid, GAGs, including pentosan, collagen type II, tetracyclines or tetracycline-like compounds, diacerin, super oxide dismutase, L-ergothioneine, methylsulfanylmethane, one or more avocado/soybean unsaponifiables, and an analgesic, e.g., acetaminophen, and to methods of treating humans and animals by administration of these novel compositions to humans and animals in need thereof.

1 . A formulation for modulating inflammation associated with damage to connective tissue in humans and animals, comprising: 
 one or more avocado/soybean unsaponifiables;    an aminosugar; and    a glycosaminoglycan component,    wherein the amounts of the one or more avocado/soybean unsaponifiables, glucosamine, and glycosaminoglycan component in the formulation are effective in combination to at least one of: 
 substantially inhibit or downregulate gene expression of at least one of COX-2, TNF-α, IL-1β, iNOS, p38, and chemokines; and  
 reduce PGE-2 levels.  
   
   
   
       2 . The formulation of  claim 1 , wherein the amounts of the one or more avocado/soybean unsaponifiables, aminosugar, and glycosaminoglycan in the formulation are effective in combination to substantially inhibit gene expression of at least one of COX-2, TNF-α, iNOS, p38, IL-1β, and chemokines in tissue cells.  
   
   
       3 . The formulation of  claim 2 , wherein the tissues cells are selected from the group consisting of chondrocytes, macrophage monocytes, and fibroblasts.  
   
   
       4 . The formulation of  claim 1 , further comprising methylsulfanylmethane (MSM).  
   
   
       5 . The formulation of  claim 1 , wherein the one or more avocado/soybean unsaponifiables comprises one or more phytosterols.  
   
   
       6 . The formulation of  claim 5 , wherein the phytosterols are selected from the group consisting of campesterol, stigmasterol, dihydro-brassisterol, and Beta-sitosterol.  
   
   
       7 . The formulation of  claim 1 , wherein the formulation is in the form of a powder, and wherein the powder is created by combining the one or more avocado/soybean unsaponifiables with one or more excipients or carriers.  
   
   
       8 . The formulation of  claim 1 , wherein the aminosugar is natural, synthetic or semi-synthetic.  
   
   
       9 . The formulation of  claim 1 , wherein the one or more avocado/soybean unsaponifiables is natural, synthetic or semi-synthetic.  
   
   
       10 . The formulation of  claim 1 , wherein the aminosugar has been chemically modified by one or more of esterification, sulfation, polysulfation, acetylation and methylation.  
   
   
       11 . The formulation of  claim 1 , wherein the aminosugar is selected from the group consisting of glucosamine, glucosamine salts, and mixtures thereof.  
   
   
       12 . The formulation of  claim 1 , wherein the aminosugar is selected from the group consisting of glucosamine hydrochloride, glucosamine sulfate, glucosamine phosphate, mannosamine and salts of N-acetylglucosamine.  
   
   
       13 . The formulation of  claim 1 , wherein the glycosaminoglycan component comprises a natural, synthetic or semi-synthetic glycosaminoglycan, a glycosaminoglycan-like compound, a glycosaminoglycan precursor or fragments of a glycosaminoglycan.  
   
   
       14 . The formulation of  claim 1 , wherein the glycosaminoglycan component has been chemically modified by one or more of esterification, sulfation, polysulfation, acetylation and methylation.  
   
   
       15 . The formulation of  claim 1 , wherein the glycosaminoglycan component is selected from the group consisting of chondroitin, chondroitin salts, hyaluronic acid, pentosan polysulfate and mixtures thereof.  
   
   
       16 . The formulation of  claim 1 , wherein the glycosaminoglycan component is chondroitin sulfate.  
   
   
       17 . The formulation of  claim 1 , wherein a dose of the one or more avocado/soybean unsaponifiables ranges from about 5 milligrams to about 5 grams.  
   
   
       18 . The formulation of  claim 1 , wherein a dose for a small animal of the one or more avocado/soybean unsaponifiables ranges from about 5 milligrams to about 1000 milligrams.  
   
   
       19 . The formulation of  claim 1 , wherein a dose for a human of the one or more avocado/soybean unsaponifiables ranges from about 25 milligrams to about 1500 milligrams.  
   
   
       20 . The formulation of  claim 1 , wherein a dose for a large animal of the one or more avocado/soybean unsaponifiables ranges from about 100 milligrams to about 5 grams.  
   
   
       21 . The formulation of  claim 1 , wherein a dose of the one or more avocado/soybean unsaponifiables ranges from about 0.5 mg/kg to about 25 mg/kg.  
   
   
       22 . The formulation of  claim 1 , wherein a dose of the one or more avocado/soybean unsaponifiables for a small animal ranges from about 0.5 mg/kg to about 25 mg/kg.  
   
   
       23 . The formulation of  claim 1 , wherein a dose of the one or more avocado/soybean unsaponifiables for a human ranges from about 0.5 mg/kg to about 25 mg/kg.  
   
   
       24 . The formulation of  claim 1 , wherein a dose of the one or more avocado/soybean unsaponifiables for a large animal ranges from about 0.5 mg/kg to about 25 mg/kg.  
   
   
       25 . The formulation of  claim 1 , wherein a dose of the aminosugar ranges from about 25 milligrams to about 12 grams.  
   
   
       26 . The formulation of  claim 1 , wherein a dose for a small animal of the aminosugar ranges from about 25 milligrams to about 3 grams.  
   
   
       27 . The formulation of  claim 1 , wherein a dose for a human of the aminosugar ranges from about 100 milligrams to about 4 grams.  
   
   
       28 . The formulation of  claim 1 , wherein a dose for a large animal of the aminosugar ranges from about 300 milligrams to about 15 grams.  
   
   
       29 . The formulation of  claim 1 , wherein a dose of the aminosugar ranges from about 3 mg/kg to about 125 mg/kg.  
   
   
       30 . The formulation of  claim 1 , wherein a dose of the aminosugar for a small animal ranges from about 3 mg/kg to about 125 mg/kg.  
   
   
       31 . The formulation of  claim 1 , wherein a dose of the aminosugar for a human ranges from about 3 mg/kg to about 125 mg/kg.  
   
   
       32 . The formulation of  claim 1 , wherein a dose of the aminosugar for a large animal ranges from about 3 mg/kg to about 125 mg/kg.  
   
   
       33 . The formulation of  claim 1 , wherein a dose of the glycosaminoglycan component ranges from about 15 milligrams to about 12 grams.  
   
   
       34 . The formulation of  claim 1 , wherein a dose of the glycosaminoglycan component for a small animal ranges from about 15 milligrams to about 2 grams.  
   
   
       35 . The formulation of  claim 1 , wherein a dose of the glycosaminoglycan component for a human ranges from about 75 milligrams to about 4 grams.  
   
   
       36 . The formulation of  claim 1 , wherein a dose of the glycosaminoglycan component for a large animal ranges from about 300 milligrams to about 12 grams.  
   
   
       37 . The formulation of  claim 1 , wherein a dose of the glycosaminoglycan component ranges from about 1 mg/kg to about 75 mg/kg.  
   
   
       38 . The formulation of  claim 1 , wherein a dose of the glycosaminoglycan component for a small animal ranges from about 1 mg/kg to about 75 mg/kg.  
   
   
       39 . The formulation of  claim 1 , wherein a dose of the glycosaminoglycan component for a human ranges from about 1 mg/kg to about 75 mg/kg.  
   
   
       40 . The formulation of  claim 1 , wherein a dose of the glycosaminoglycan component for a large animal ranges from about 1 mg/kg to about 75 mg/kg.  
   
   
       41 . The formulation of  claim 1 , wherein the formulation is prepared for intramuscular, intravenous, oral, subcutaneous, rectal, topical, transcutaneous, intranasal, intraarticular, sublingual and intraperitoneal administration.  
   
   
       42 . The formulation of  claim 1 , wherein the formulation is prepared for administration in the form of one or more pills, one or more tablets, one or more capsules, one or more creams, powders, liquid form, aerosol form, extended release form, or in the form of an injectable.  
   
   
       43 . The formulation of  claim 1 , wherein the formulation is prepared for administration in the form of one or more liquid-filled capsules, one or more softgel capsules, a paste, chewable tablets, one or more scoops of powder, one or more sachets, or one or more treats.  
   
   
       44 . A method of preventing, treating, managing, repairing or modulating inflammation associated with damage to connective tissue in humans and animals comprising administering the formulation of any of  claims 1  to  43  to a human or animal in need thereof.  
   
   
       45 . A method of preventing, treating, managing, repairing or modulating inflammation associated with damage to connective tissue in humans and animals comprising administering the formulation of  claim 1  to a human or animal in need thereof, wherein the formulation is administered daily to reach a steady state concentration in a body fluid of the human or animal that bathes a target cell type that affects at least one of COX-2, TNF-α, IL-1β, iNOS, p38, and chemokines, and wherein the dosage is subsequently reduced in at least one of frequency and amount to maintain a desired response in the human or animal.  
   
   
       46 . The formulation of  claim 1 , wherein the one or more avocado/soybean unsaponifiables are standardized to about 30% sterol.  
   
   
       47 . The formulation of  claim 1 , wherein the one or more avocado/soybean unsaponifiables are standardized to about 30% sterol in approximately a 2-1 ratio of soybean unsaponifiables to avocado unsaponifiables.  
   
   
       48 . The formulation of  claim 1 , wherein the one or more avocado/soybean unsaponifiables are a solid at room temperature and a liquid at human body temperature.  
   
   
       49 . The formulation of  claim 1 , wherein the amounts of the one or more avocado/soybean unsaponifiables, glucosamine, and glycosaminoglycan component in the formulation are effective in combination to substantially inhibit or downregulate gene expression of one or more chemokines, wherein the one or more chemokines are selected from the group consisting of IL-8 and MCP.  
   
   
       50 . The formulation of  claim 1 , wherein the amounts of the one or more avocado/soybean unsaponifiables, glucosamine, and glycosaminoglycan component in the formulation are effective in combination to reduce a level of PGE-2.  
   
   
       51 . The formulation of  claim 1 , wherein the amount of the one or more avocado/soybean unsaponifiables is selected to achieve a level of about 8 to about 25 μg/mL of body fluid that bathes a target cell type that affects at least one of COX-2, TNF-α, IL-1β, iNOS, p38, and chemokines.  
   
   
       52 . The formulation of  claim 1 , wherein the aminosugar comprises glucosamine in a concentration effective to achieve a dosage of about 10 μg/mL in the target human or animal, and wherein the glycosaminoglycan component comprises chondroitin sulfate in a concentration effective to achieve a dosage of about 20 μg/mL in the target human or animal.  
   
   
       53 . A method of modulating markers of inflammation of connective tissue in a target human or animal, comprising: 
 administering a composition comprising one or more avocado/soybean unsaponifiables, glucosamine, and chondroitin sulfate to a human or animal, wherein the composition is administered to the target human or animal to modulate inflammation in an amount effective to moderate gene expression of at least one of COX-2, TNF-α, IL-1β, iNOS, p38, and chemokines to approximately normal values.    
   
   
       54 . A formulation for modulating inflammation associated with damage to connective tissue in humans and animals, comprising: 
 one or more avocado/soybean unsaponifiables;    an aminosugar component comprising comprising glucosamine, glucosamine salts, or mixtures thereof, and    a glycosaminoglycan component comprising chondroitin, chondroitin salts, or mixtures thereof,    wherein the amounts of the one or more avocado/soybean unsaponifiables, aminosugar component, and glycosaminoglycan component in the formulation are effective in combination to substantially inhibit or downregulate gene expression of COX-2, TNF-α, IL-1β, iNOS, p38, and chemokines, and to reduce PGE-2 levels.