Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-04-22
2003-11-11
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C514S062000, C536S053000, C530S350000, C623S016110
Reexamination Certificate
active
06645945
ABSTRACT:
BACKGROUND OF THE INVENTION
Hyaluronic acid is a naturally-occurring polysaccharide containing alternating N-acetyl-D-glucosamine and D-glucuronic acid monosaccharide units linked with beta 1-4 bonds and the disaccharide units linked with beta 1-3 glycoside bonds. It occurs usually as the sodium salt and has a molecular weight range of about 50,000 to 8×10
6
.
The joint cavity or synovium is filled with synovial fluid which is predominantly made up of hyaluronic acid (HA). The HA of the synovium is produced primarily by the synoviocytes that line the intima layer of the synovium, and proteins and nutrients that are drawn from the lymphatic system. The synovial fluid is a liquid form of an extracellular matrix that maintains the synovium volume and hydrostatic pressure, provides chondrocytes in the avascular particular cartilage with a steady flow of nutrients, lubricates the cartilage surface, and cushions the synovial tissue from the deforming forces of movements, (Unsworth, A., “Mechanics of Human Joints”, (eds, Wright, V., and Radin, E. L.), pp 137-162, Marcel Dekker, New York, 1993). The rheological properties of synovial fluid are the result of the intricate meshwork of high molecular weight HA and its interaction with water molecules. It is a high molecular weight polymer made up of repeating disaccharide units of N-acetyl-glucosamine and glucuronic acid, Meyer, K., and Palmer, J. W., J. Biol. Chem. 107: 629-634, 1934.
The molecule is synthesized at the plasma membrane by the recently cloned hyaluronan synthase complex (Naoki, I., and Kimura, K., J. Biol. Chem., 271: 9875-9878, 1996 and Spicer, A. P. and McDonald, J. A., J. Biol. Chem., 273: 1923-1932, 1998). In a typically newly synthesized chain, upwards to 5000 disaccharide's units are present, though it is currently unclear how the newly synthesized chain lengths are determined. Hyaluronan turnover in normal human synovial fluid is estimated to be approximately 20 hours, (Laurent, T. C., Laurent, U. B. G., and Fraser, J. R. E., Ann. Rheum. Dis., 54: 429-432, 1995).
Osteoarthritis (OA) is a common joint disease of unknown etiology. The pathology of OA is characterized by a progressive loss of the particular cartilage of synovial joints with concomitant bony changes, including sclerosis and osteophyte formation (Yelin, E., “Osteoarthritis” (eds. Brandt, K., Doherty, M., and Lohmander, L. S.), pp. 23-30, Oxford University Press, New York, 1998; Flores, R. H., and Hochberg, M. C., “Osteoarthritis” (eds. Brandt, K., Doherty, M., and Lohmander, L. S.), pp. 1-12, Oxford University Press, New York, 1998). In some cases, hyperthrophy of the marginal and underlying bone, mild synovitis and capsular thickening are observed (Flores et al.). Initiation events for OA are unknown but recent findings indicate that the onset of this disease is highly dependent on the balance between mechanical stability of the joint and the degree of mechanical insult or injury. It has been postulated that mechanical instability of the joint will lead to a failure of the resident cartilage cells, known as chondrocytes, to maintain the balance between synthesis and degradation of the extracellular matrix. Ultimately, this homeostasis fails and the degradation process begins to outweigh new synthesis (Lohmander, L. S., “Osteoarthritic Disorders” (eds Kuettner, K. E., and Goldberg, V. M.), pp. 459-474, The American Academy of Orthopedic Surgeons, Rosemond 1995). The disease is particularly debilitating and disabling and is not easily treated at the time of detection. Early diagnosis is often difficult because of:
1) the lack of sensitive and cost permitting methods for early detection; and
2) the tendency of patients to attribute joint pain to the gradual but inevitable part of aging (Brandt, K., Lohmander, L. S., and Doherty, M., “Osteoarthritis” (eds. Brandt K., Doherty, M., and Lohmander, L. S.), pp. 70-74, Oxford University Press, New York, 1998). Consequently, this highly debilitating and degenerative disease is often not diagnosed until late stages of the disease that present clinical and radiographic manifestations. Current treatments or therapy are only palliative and designed to reduce pain and physical disability. Most medications that are in current use non-steroidal anti-inflammatory drugs (NSAIDs) which are often ineffective and in some instances have deleterious effects on cartilage metabolism (Brandt, K., D. Rheum. Dis., North Am., 19: 697-712, 1993). Most health care providers and afflicted patients are more interested in relieving the painful symptoms and disability associated with this disease. In view of a lack of curative treatment for OA, it is imperative that any current therapy being developed for this disease be aimed at relieving these debilitating and disabling symptoms.
The biochemistry and factors that regulate the metabolism of the joint, in particular particular cartilage, are a crucial part of the scientific rationale for designing a new treatment for OA. Particular cartilage is composed of an intricate collagenous scaffold that consists mainly of type II collagen, with types VI, XI and XI collagen found in specific locations throughout the matrix (Ronziere, M. C., Ricard-Blum, S., Tollier, J. et al, Biochim. Biophys. Acta, 1038: 222-230, 1990 and Eyre, D., Wu, J. J., and Woods, P., “Particular Cartilage and Osteoarthritis”, (eds, Keuttner, K. E., Schleyerbach, R., Peyron, J. G., and Hascall, V. C.), pp. 119-131, Raven Press, New York, 1992). Within this matrix are found, large multi-ternary complexes, known as proteoglycan aggregates. These complexes are made up of an HA backbone and aggrecan molecules that interact specifically, in a non-covalent manner, via core protein sequences, that are also stabilized by a co-operative interaction with link protein (Goetinck, P. F., Stirpe, N. S., Tsonis, P. A., and Carlone, D., J. Cell Biol., 105: 2403-2408, 1987 and Hascall V. C., and Heinegard, D., J. Biol. Chem., 249: 4232-4241, 1974). The multiple glycosaminoglycan (GAG) chains on aggrecan are made up of mostly of chondroitin sulfate (approx. 100 chains of 15-20 kDa), and keratin sulfate (up to 50 chains of 5-8 kda) and confer the specialized viscoelastic and biomechanical properties of particular cartilage tissue (Hascall, V. C., “Atlas of Science: Biochemistry”, (ed. Grimmwade), pp. 189-198, New York, 1988). As such, the concentration of GAGS and their anionic character, coupled with the integrity of the collagen meshwork, are the primary parameters that define the unique Theological properties of particular cartilage (Torchia, D. A., Hasson, M. A., and Hascall, V. C., J. Biol. Chem., 251: 3617-3625, 1977). It is, therefore, important that the metabolic regulation of these molecules by chondrocytes be maintained at a level that permits the tissue to function properly.
In normal cartilage, chondrocytes actively maintain a stable equilibrium between the synthesis and degradation of matrix components. In degenerative joint diseases like OA, this equilibrium is disrupted as the rate of proteoglycan and matrix loss begins to exceed the rate of deposition of newly synthesized molecules (Handley, C. J., “Particular Cartilage and Osteoarthritis”, (eds, Keuttner, K. E., Schleyerbach, R., Peyron, J. G., and Hascall, V. C.), pp. 411-413, Raven Press, New York, 1992). Various factors are known to modulate and regulate proteoglycan aggregate complex metabolism in particular cartilage. Anabolic factors such as insulin-like growth factor-I (IGF-I) (Morales, T. I., and Hascall, V. C., Ann. Rheum., 32: 1197-1201, 1989; McQuillan, D. J., Handley, C. J., Campbell, M. A. et al., Biochem. J., 240: 423-430, 1986 and Luyten, F. P., Hascall, V. C., Nissley, S. P. et al., Arch. Biochem. Biophys., 267: 416-425, 1988, and growth differentiation factor-5 (GDF-5), Erlacher, L., Ng, C. K., Ullrich, R. et al., Arthr. Rheum., 41: 263-273, 1998), are of particular interest as specific mitogens that also promote the synthesis of proteoglycans and other matrix proteins in chondrocytes.
The IGFs are polypeptides that share structural and functional
Heidaran Mohammad A.
Radomsky Michael
Beyer Weaver & Thomas
DePuy Acromed, Inc.
Fonda Kathleen K.
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