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(12) United States Patent (10) Patent No.: US 6,492,429 B1 Graus Et Al

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(12) United States Patent (10) Patent No.: US 6,492,429 B1 Graus Et Al USOO6492429B1 (12) United States Patent (10) Patent No.: US 6,492,429 B1 Graus et al. (45) Date of Patent: Dec. 10, 2002 (54) COMPOSITION FOR THE TREATMENT OF 5,401.777 A 3/1995 Ammon et al. OSTEOARTHRITIS 5,494.668 A 2/1996 Patwardhan 5,629,351 A 5/1997 Taneja et al. (75) Inventors: Ivo Maria Franciscus Graus, Wg Ede 5,872,124. A * 2/1999 Koprowski et al. ......... 514/261 (NL); Hobbe Friso Smit, As Utrecht 5,888,514 A * 3/1999 Weisman ................. 424/195.1 (NL) FOREIGN PATENT DOCUMENTS (73) Assignee: N.V. Nutricia, Zoetermeer (NL) WO 95 22323 8/1995 WO 97 O7796 3/1997 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Balch et al. Prescription for Nutritional Healing; Avery Publishing 2nd Ed. pp. 138–144, Oct. 1997.* (21) Appl. No.: 09/662,123 Lafeber et al., “Apocynin, a plant-derived, cartilage-Saving drug, might be useful in the treatment of rheumatoid (22) Filed: Sep. 14, 2000 arthritis", Rheumatology, (1999), pp. 1088–1093, vol. 38, O O British Society for Rheumatology. Related U.S. Application Data * cited by examiner (63) Continuation of application No. 09/613,562, filed on Jul. 10, 2000. Primary Examiner-Christopher R. Tate 7 ASSistant Examiner Patricia A Patten (51) Int. Cl." ......................... A01N 35/00; AO1N 65/00 (74) Attorney, Agent, or Firm-Browdy and Neimark, (52) U.S. Cl. ........................................ 514/688; 424/725 PL.L.C. (58) Field of Search ........................... 424/195.1, 196.1, 424/523, 547; 514/54, 62, 365, 783, 688; (57) ABSTRACT 260/468, 294.8, 470 Osteoarthritis is treated by a composition containing both (56) References Cited apocynin and an inhibitor of inducible nitric oxide synthase Such as curcumin. Further components Such as boswellic U.S. PATENT DOCUMENTS acids, glucosamine, acetylcysteine and boron further 3,950,387 A * 4/1976 Joullie et al. ............... is enhance the beneficial effect of apocynin and curcumin. 4,315,028 A * 2/1982 Scheinberg ................. 424/290 5,120,538 A 6/1992 Oei ......................... 424/195.1 8 Claims, No Drawings US 6,492.429 B1 1 2 COMPOSITION FOR THE TREATMENT OF (4-hydroxy-3-methoxy-acetophenone, acetovanillone) for OSTEOARTHRITIS the treatment of rheumatoid arthritis. WO95/22323 describes the use of analogues of apocynin, CROSS REFERENCE TO RELATED in particular the 4-hydroxyethoxy analogue, for controlling APPLICATION free radical generation by inflammatory cells in e.g. inflam The present application is a continuing application from matory bowel disease, rheumatoid arthritis and Several other copending application Ser. No. 09/613,562, filed Jul. 10, inflammatory conditions. 2OOO. U.S. Pat. No. 5,629,351 discloses a fraction of boswellic FIELD OF THE INVENTION acids isolated form BOSwellia Serrata, including a hitherto unknown 2-hydroxybos wellic acid, having anti The invention is concerned with compositions for the inflammatory, anti-arthritic and anti-ulcerogenic activities. treatment of Osteoarthritis and related diseases and with WO 97/07796 claims the use of boswellic acid for the methods for treating osteoarthritis. treatment of diseases, Such as lung emphysema, cystic BACKGROUND OF THE INVENTION fibrosis, rheumatoid arthritis etc., which are induced by 15 leucocytic elastase or plasmin activity. Osteoarthritis (OA) is a degenerative joint disease, which develops by wear and tear of the joints during aging. OA U.S. Pat. No. 5,401,777 relates to the use of curcumin for mostly affects the weight-bearing joints Such as Spine, knees treating conditions associated with formation of leucotrienes and hips, but thumb and finger joints may also be affected. from arachidonic acid, Such as inflammatory bowel diseases, Repetitive mechanical injury of the cartilage eventually chronic hepatitis, bronchial asthma and psoriasis. results in loss of cartilage and damage to joint Surfaces and U.S. Pat. No. 5,494,668 describes a product to be used for adjacent bone. As a result of the tissue destruction, inflam the treatment of OA and other musculoskeletal diseases, matory cells invade the joint and the Synovial membrane containing combined extracts from Withania SOmnifera which is manifested by pain, Swelling and Stiffness of the (Ashwaganda) roots, Boswellia Serrata (Sallaiguggul) gum affected joints. The repetitive mechanical injury leads to 25 exudate (boSwellic acids), Curcuma longa (turmeric) rhi pathological changes that result in loSS of proteoglycans and Zomes (curcumin) and Zingiber officinale (ginger). collagen from the cartilage matrix, which in turn leads to SUMMARY OF THE INVENTION Surface erosion and decreased loading capacity, In OA, chondro-cytes show a reduced potential to Synthesize matrix It was found that osteoarthritis can be effectively treated constituents (proteoglycans and collagen fibers) and the by administration of a Suitable amount of apocynin or its expression of proteolytic enzymes (called matrix metallo functional and structural analogues, preferably in the form of proteases, MNMPs) contributes to cartilage destruction and an extract from a Picrorhiza plant, and preferably together release of proteoglycan fragments in the Synovial fluid. The with further components enhancing the beneficial effect of inflammatory responses to the mechanical insults further the apocynin. Thus, the invention in a first aspect provides contribute to cartilage destruction. The inflammatory media 35 compositions for the treatment of Osteoarthritis, containing tor interleukin I (IL-1) is considered as the principal media an effective amount of apocynin or its analogues. tor of cartilage destruction. It induces a number of changes In a Second aspect, the invention provides methods for in chondrocytes, including the concurrent generation of treating Osteoarthritis comprising administering to a perSon Significant amounts of NO (nitrogen oxide) and Superoxide in need of Said treatment an effective amount of apocynin or radicals by inducible NO synthase (iNOS) and NADPH 40 its analogues. In a third aspect, the invention provides oxidase, respectively. NO reacts with Superoxide to form compositions comprising apocynin or analogues and meth peroxynitrite, which is largely responsible for the decrease ods for the treatment of arthritis in general as caused by in proteoglycan Synthesis induced by IL-1. The role of wear-and-tear processes, due to labour, ageing or obesity, for Superoxide was further demonstrated by the ability of Super the treatment of developed arthritis and for the-treatment of oxide dismutase to reverse the decrease in proteoglycan 45 the first Symptoms of joint disorders in patients not having Synthesis. The prevention of peroxynitrite formation via a familial history of rheumatism. Selective inhibition of iNOS and thus NO formation in vivo In a fourth aspect the invention provides compositions resulted in a marked decrease of MMPs. In addition, that are characterized by the Simultaneous presence of intra-articular treatment of OA patients with Superoxide apocynin or analogues and other components, in particular dismutase reduces Symptoms of OA for prolonged periods. 50 an inhibitor of inducible nitric oxide synthase and methods These Studies demonstrate that induction of catabolic for treatment of arthritis in general caused by wear-and-tear, enzymes (MMPs) and cartilage destruction is mediated via autoimmune responses in the joints, goute, or other causes of the formation of NO and Oradicals by chondrocytes or cartilage degradation. inflammatory cells. While the primary cause of OA is DETAILED DESCRIPTION OF THE mechanical damage, rheumatoid arthritis (RA) is mainly the 55 result of an autoimmune response that leads to chronic INVENTION inflammation in the joint. Contrary to OA, typical manifes According to the invention apocynin is a highly useful tations of RA are an increase of parameters that are associ component for treating osteoarthritis and related conditions. ated with inflammation, Such as haematocrite and white In particular, apocynin was found to be effective in retarding blood cell count and pannus formation or hyperplasia of the 60 progression of Osteoarthritis. It was found furthermore, that joint capsule that leads to deformed joints. This in turn leads the inflammatory processes in arthritis can be controlled and to morning Stiffness. Although the (primary) aetiology of RA the accompanying Symptoms of Stiffness and pain can be and OA are different, the pathological processes at a later alleviated by combined administration of an inhibitor of Stage result in Some manifestations that are similar Such as NADPH oxidase, such as apocynin, and an inhibitor of joint pain, cartilage degradation and general joint disability. 65 inducible nitric oxide synthase (iNOS), such as curcumin. Lafeber et al. (Rheumatology, 1999 (38) 1088–1093) Consequently, the composition of the invention contains describe in vitro Studies on the utility of apocynin at least 50 lug, preferably at least 100 tug, up to 1000 mg of US 6,492.429 B1 3 4 apocynin on the basis of daily intake. The preferred daily CO-, p-coumaroyl), preferably a 3,4-di-hydroxycinnamoyl intake is between 1 and 100 mg. Apocynin (acetovanillone) (caffeoyl) or 4-hydroxy-3-methoxycinnamoyl (feruloyl) is a known compound (4-hydroxy-3-methoxy group, and/or a dihydroxyphenyl group, preferably a dihy acetophenone); most preferred is a dosage of at least 15 droxybenzopyran group, were found to be useful in this mg/day. According to the invention, analogues of apocynin
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