Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-04-25
2003-10-14
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06632804
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to therapeutic compositions for use in treating diseases of connective tissues in animals, more particularly, for use in treating osteoarthritis in mammals, such as humans, dogs, cats, pigs, horses, cows, goats and sheep.
BACKGROUND OF THE INVENTION
Arthritic diseases, characterized by the pain, inflammation and stiffness of the joints leading to reduced range of mobility, are due to the degradation of connective tissue (mainly cartilage) in joints. Such diseases particularly affect weight-bearing joints such as the hips, knees, spine, ankles and feet and those joints with frequent movement such as hands, arms and neck.
Osteoarthritis (OA) in particular is a degenerative disease of the joint cartilage resulting in narrowing of the joint space and changes in the underlying bone (Barclay, et al.,
The Annals of Pharmacotherapy,
(May, 1998) 32: 574-79). OA is the most common form of arthritis among people and it affects approximately one in ten people in North America. People of all ages can get OA, but it more often affects older people and women. For example, 85% of the age group 70 years or older is affected by OA (The Arthritis Society website, (http://www.arthritis.ca), Feb. 4, 2000, published by The Arthritis Society). OA is not limited to humans, but occurs in other mammals such as horses, dogs, cats, mice and guinea pigs as well, making OA one of the most common sources of chronic pain seen by veterinarians.
The cause of OA could be one or more of the following: nutritional deficiencies, aging, long-term stress on joints (e.g. athletes, manual workers), old joint injuries and genetic factors. The tissue that is directly affected is the cartilage covering the end of long bones in joints that provide cushioning for the bones during movements. In normal cartilage, chondrocytes (cartilage cells) maintain a balance between the synthesis and degradation of cartilage matrix. However, when the degradation of cartilage matrix exceeds that of synthesis, it leads to OA. When the disease progresses further, bone underlying the articular cartilage in joints becomes exposed in certain places. In addition, irregular bone growth occurs in the place of degenerating cartilage resulting in rough bony alterations. As a result, the joint loses its smooth functioning leading to joint pain, stiffness and swelling thus limiting mobility.
Cartilage is a unique tissue having cells (chondrocytes) embedded in their own secretions which forms the cartilage matrix. The cartilage matrix is composed of a meshwork of collagen fibrils and proteoglycan aggregates filling the space between collagen. Collagen fibrils provide high tensile strength and proteoglycan aggregates provide internal swelling pressure due to their hydrophilic nature. Cartilage cells are remarkable in that they have the ability to proliferate while synthesizing and remodeling the matrix around them. These two features provide the cartilage the ability to repair itself during damage and replenish wear and tear.
Collagen fibrils are a major component of the cartilage matrix. Collagen is made from amino acids, particularly lysine, proline and glycine. Fibrillar collagens are triple helical molecules. The three &agr;-chains of each collagen molecule are initially produced as individual peptides which are further processed by the hydroxylation of proline and lysine residues bound to the peptides. The hydroxyproline and hydroxylysine so produced facilitate hydrogen bonding between the three &agr;-chains, this being essential for the formation of the triple helical structure (Linsenmayer,
Collagen,
Chapter 1 in
Cell Biology of Extracellular Matrix, Second Edition,
Elizabeth D. Hay, ed., Plenum Press, N.Y. (1991) pp. 7-13). Unlike individual collagen peptides (&agr;-chains) that become easily digested by proteolytic enzymes, triple helical collagen is extremely stable to proteolytic enzymes, heat and variations of pH. Therefore, the most important step in collagen synthesis is the formation of the triple helical structure by hydroxylation of amino acids in collagen &agr;-chains. While the Linsenmayer reference suggests that ascorbic acid and ferrous ions are cofactors in the hydroxylation of proline and lysine to hydroxyproline and hydroxylysine respectively, Linsenmayer does not suggest that a therapeutic composition comprising ascorbic acid and ferrous ions would be useful in the treatment of osteoarthritis.
Proteoglycan aggregates are the other major component of the cartilage matrix. Cartilage proteoglycans are macromolecules comprised of glycosaminoglycan (GAG) chains, such as chondroitin sulphate and keratan sulphate, that are made up of repeating disaccharide units containing aminosugars, attached to a core protein. Proteoglycans are in turn attached to a backbone of hyaluronic acid, which is yet another GAG. Among GAGs of cartilage, hyaluronic acid is unique in that it is an extremely large molecule with about 25,000 repeating disaccharide units (in comparison, chondroitin sulphate and keratan sulphate have only about 250 and 80 repeating disaccharide units respectively). About 50% of hyaluronic acid and keratan sulphate are glucosamine.
Rheumatoid arthritis (RA) is a disease that has some similar symptoms to osteoarthritis, but whose cause is considerably different. RA is known to be an autoimmune disease (Maini, et al.,
Aetiopathogenesis of Rheumatoid Arthritis.
in
Mechanisms and Modes of Rheumatoid Arthritis,
(1995) Academic Press Ltd. pp. 25-46), in which the immune system attacks body tissues as if they were foreign invaders, culminating in inflammatory and destructive responses in joints as well as other tissues. Although the exact cause of RA is not completely understood, contributing factors are believed to include food allergies, pathogens, leaky gut syndrome and hereditary factors. Because of the difference in cause of RA as opposed to diseases of the connective tissues such as osteoarthritis, it is not necessarily expected that treatment for RA would be effective against osteoarthritis and the like.
A number of treatments for osteoarthritis and like diseases are commonly used. Most of the treatments currently available are aimed towards reducing symptoms but do not deal with the underlying tissue degradation. The use of steroids, corticosteroids and other anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs (NSAIDs), for example, aspirin™, relieve symptoms and reduce pain but also do not deal with the underlying tissue degeneration. NSAIDs may even speed up the progression of OA (Rashad et al.,
The Lancet,
(September, 1989) 2: 519-521, and, Herman et al.,
The Journal of Rheumatology,
(1986) 13: 1014-1018).
Therapies based on the regeneration of connective tissue, particularly cartilage, are attractive long-term solutions to the problem of osteoarthritis. To this end, there have been a number of disclosures of therapeutic compositions for the treatment of arthritic diseases.
U.S. Pat. Ser. No. 3,683,076 issued on Aug. 8, 1972 to Rovati discloses pharmaceutical compositions comprising the glucosamine salts—glucosamine sulphate and glucosamine hydroiodide—for the treatment of osteoarthritis and rheumatoid arthritis.
U.S. Pat. Ser. No. 5,587,363 issued on Dec. 24, 1996 to Henderson discloses therapeutic compositions comprising a synergistic combination of certain aminosugars (glucosamine and its salts) with GAG's (chondroitin and its salts) for the repair and replacement of connective tissue. Henderson suggests that Zn, Mn and Vitamin C play a role in the synthesis of procollagen which is a building block of collagen and that Cu, Fe and Vitamin C play a role in the synthesis of collagen from procollagen. However, Henderson does not disclose synergistic compositions of ferrous ion and an ascorbate. Henderson further suggests that glucosamine is a building block in the synthesis of procollagen and that procollagen is a building block in proteoglycan synthesis. However, it is generally accepted that glucosamine is not a building block of procollagen
Fonda Kathleen K.
Ocean Nutrition Canada Limited
Welsh & Katz Ltd.
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