Drug – bio-affecting and body treating compositions – Arthritis
Patent
1986-11-04
1989-01-31
Griffin, Ronald W.
Drug, bio-affecting and body treating compositions
Arthritis
514 54, 536 551, C08B 3705, A61K 31725
Patent
active
048016195
DESCRIPTION:
BRIEF SUMMARY
This invention relates to high-molecular-weight hyaluronic acid having a molecular weight exceeding 3.times.106 dalton and intended for use as an agent for counteracting progressive cartilage destruction as, caused by degradation of proteoglycans. The type of treatment here referred to is intended for mammals, including man.
The term "hyaluronic acid", as employed here, refers both to the acid as such and to its physiologically acceptable salt, unless stated otherwise.
The quantitatively predominant part of articular cartilage consists of an extracellular matrix, which plays an important functional role and the composition of which is controlled by a relatively small number of cells. This matrix is composed of (i) collagen forming a fibrous network which is of importance for the volume stability of the tissue, and (ii), proteoglycans as a further major component, having a large amount of mutually repellent electric charges due to which the tissue acquires its elasticity and its ability to resist compression. Moreover, articular cartilage contains several other proteins, generally without known functions. An exception to this are the link proteins which participate in the formation of proteoglycan aggregates and contribute to the stability of these aggregates. Such aggregate formation is a necessary prerequisite for the fixation of the proteoglycans and its negatively charged groups in the tissue.
Degradation of the structures in articular cartilage is a typical characteristic of all diseases resulting in chronic destruction of the joint structures. Examples of such disorders are rheumatoid arthritis, psoriatic arthritis, and osteoarthrosis. Also, acute inflammation of a joint is often accompanied by destruction of the cartilage, although in most cases this will not develop into the chronically destructive disease. It is not known which factors are crucial for the acutely inflamed joint to either proceed to healing or develop into the chronic process. Examples of diseases involving acute joint inflammation are yersinia arthritis, pyrophosphate arthritis, gout arthritis (arthritis urica), septic arthritis and various forms of arthritis of traumatic etiology. Among other factors potentially conducive to the destruction of articular cartilage may be mentioned, for instance, treatment with cortisone; this has been known for a long time to accelerate the degenerative process in osteoarthrosis. Such a so-called "steroid arthropathy" occurs far too often as an undersirable side effect of intra-articular cortisone treatment and can be avoided only by providing for a sufficiently long period of rest after the treatment. Steroid arthropathy is characterized by an advanced degree of articular destruction and X-ray-detectable changes of the same type as occur in advanced degenerative articular disease (Nizolek, DH & White, KK, Cornell Vet. 1981, 71:355-75). According to what is at present accepted as an explanation of the degenerative arthropathy development following treatment with cortisone, this arthropathy is believed to be caused by a primary effect on the chondrocyte metabolism. It should be noted, however, that the actual conditions prevailing in cases of arthritis with severe inflammation of the joint are of a rather more complex character, since in those cases injection of cortisone appears to have an overall positive effect on the clinical picture.
Hyaluronic acid is a naturally occurring glycosaminoglucan. Its molecular weight may vary from 50,000 dalton upwards, and it forms highly viscous solutions. As regards the actual molecular weight of hyaluronic acid in natural biological contexts, this is still a matter of much uncertainty: When the molecular weight of hyaluronic acid is to be determined, different values are obtained depending on the assay method employed, and on the source, the isolation method etc. Molecular weights given in this specification have been determined according to Int J Biol Macromol 7 (1985), p. 30-2. The acid occurs in animal tissue, e.g. spinal fluid, ocular fluid, synovial fluid,
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Research in Veterinary Science, vol. 30, No. 2, issued 1981 (Oxford), D. A. Gingerich et al., "Effect of Exogenous Hyaluronic Acid on Joint Function in Experimentally Induced Equine Osteoarthritis: Dosage Titration Studies", see pp. 192-197, especially p. 192 and pp. 196-197 (Discussion).
International Journal of Clinical Pharmacology, Therapy and Toxicology, vol. 20, No. 11, issued 1982 (Munich), O. Namiki et al., "Therapeutic Effect of Intra-Articular Injection of High Molecular Weight Hyaluronic Acid on Osteoarthritis of the Knee", see pp. 501-507, especially p. 501 and pp. 504-506 (Discussion).
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Upsala, Journal of Medical Sciences, Supplement 17. issued 1975 (Uppsala), A. Wigren et al., "Repeated Intraarticular Implantation of Hyaluronic Acid", see pp. 1-20, especially p. 3 and p. 19 (Summary).
Proceedings of the Twenty-Fourth Annual Convention of the American Association of Equine Practitioners, St. Louis, Missouri, Dec. 2-6, 1978, published 1979 by American Association of Equine Practitioners, O. G. Swanstrom, "Hyaluronate (Hyaluronate Acid) and its Use", see pp. 345-348, especially p. 345, first two paragraphs, and p. 347, second paragraph.
Griffin Ronald W.
Pharmacia AB
Philpitt Fred
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