Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-06-25
2001-06-26
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S055100
Reexamination Certificate
active
06251876
ABSTRACT:
SUMMARY OF THE INVENTION
The present invention relates to compositions containing an autocross-linked form of hyaluronic acid alone or as a first component in mixture with a second component noncross-linked hyaluronic acid, and possibly also in combination with another pharmacologically active substance. These compositions can be used in the treatment of arthropathies due to their unique viscoelastic properties.
BACKGROUND OF THE INVENTION
Hyaluronic acid (HA) is a naturally occurring polysaccharide of the glycosaminoglycan family which is present in particularly high concentration in the cartilage and synovial fluid of articular joints. It has been shown that synovial fluid acts as a viscous liquid at low shear (corresponding to the slowly moving joint) but shows an elastic behaviour at high shear (corresponding to the rapidly moving joint) (Balazs E. A., Univ. of Michigan, Med. Ctr. J. (Special Arthritis Issue), December 1968, 255). In patients with arthropathies such as osteoarthritis and rheumatoid arthritis, the viscoelastic properties of synovial fluid are compromised and this has been demonstrated to reflect a decrease of the viscoelastic contribution given by the HA component (Kobayashi Y. et al, Biorheology, 1994, 31, 235-244). This is clearly evident from
FIG. 1
which shows the Theological profiles of synovial fluid from the joints of healthy volunteers and osteoarthritic donors (“The Rheological and Biological Function of Hyaluronic Acid,” E. A. Balazs, D. A. Gibbs, in Chemistry and Molecular Biology of the Intercellular Matrix, ed. by E. A. Balazs, Academic Press, 1970). In normal synovial fluid, unlike in the case of osteoarthritis, viscoelasticity values are high and G′ and G″ cross each other. The existence of this crossover point is linked not only to the concentration of HA (2-4 mg/ml), but also, and above all, to its high molecular weight (about 4-5 million). In osteoarthritic subjects, on the other hand, there is both degradation of the hyaluronic acid, with consequent lowering of its molecular weight, and a decrease in its concentration (1-2 mg/ml).
Administration of highly purified, exogenous HA by intraarticular injection has been shown to be effective in the treatment of osteoarthritis. This is due not only to the unique viscoelastic properties of HA but also to its potential pharmacological properties. In fact, the commercial HA-based products which are currently marketed for the treatment of osteoarthritis by intra-articular injection reflect two schools of thought concerning the mode of action of HA in the treatment of these pathologies. There is strong evidence that unmodified HA exhibits pharmacological activity in addition to provoking a transient re-establishment of the viscoelastic properties of the synovial fluid (G. Abatangelo and M. O'Regan, Eur. J. Rheumatol. Inflamm., 1995, 15, 1:9-16; P. Ghosh, Clin Exp. Rheumatol., 1993, 12, 1-8; R. K. Strachan et al, An. Rheum. Dis., 1990, 49:949-952). On the other hand, manufacturers of chemically cross-linked HA derivatives promote the hypothesis that these derivatives act by solely mechanical means (E. A. Balazs and J. L. Denlinger, J. Rheumatology, 1993, vol. 20, supplement 39: 3-9).
Other forms of arthropathy besides osteoarthritis may result from modification of the viscoelastic properties of the synovial fluid of the articular joints which may occur as a result of particular mechanical or surgical operations carried out on the joint such as immobilization following joint distortion or fracture repair and joint arthroscopy. In the treatment of the functional consequences of these interventions, the lubricating potential of HA or derivatives thereof may be more pertinent than the long-term pharmacological effects of the compounds. In addition, HA is known to have a rapid turnover in the joint (Brown T. J. et al, Exp. Physiol., 1991, 76, 125-134; Fraser J. R. E. et al.; Semin. Arthritis Rheum., 1993, 22 (Suppl. 1), 9-17; Laurent U. B. G. et al., Matrix, 1992, 12, 130-6). Therefore, a further objective of the formulations described in the present invention is to increase the residence time of exogenous HA which is injected into the joints for treatment of arthropathies.
OBJECTS OF THE INVENTION
Therefore, it is an object of the present invention to provide new hyaluronic acid (HA)- and/or autocross-linked polysaccharide (ACP)-based compositions, possibly together with a suitable pharmaceutical excipient or carrier and/or drug for intraarticular use, which compositions exhibit appropriate viscoelastic properties for the treatment of arthropathies.
It is another object of the present invention to provide compositions which act as reservoirs of native HA.
Another object of the present invention is to provide a method for the treatment of arthropathies by delivering an HA- and/or ACP-based composition which exhibits appropriate viscoelastic properties and residence time within the joint and which is administered in an effective amount to a patient in need thereof.
The foregoing objects and others are accomplished in. accordance with the present invention by providing one of the following combinations:
1. an autocross-linked form of hyaluronic acid alone;
2. or an autocross-linked form of hyaluronic acid as a first component in mixtures containing, as a second component, hyaluronic acid and/or a pharmaceutically active drug for intraarticular use.
REFERENCES:
patent: WO 89/10941 (1989-11-01), None
Bellini Davide
Callegaro Lanfranco
O'Regan Michael
Paparella Annamaria
Birch & Stewart Kolasch & Birch, LLP
Fidia S.p.A.
Peselev Elli
Svensson Leonard R.
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