Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1998-05-29
2000-10-31
Peselev, Elli
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 25, 536 111, 536 171, A61K 3170, C07H 1500
Patent
active
061403075
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns pharmaceutical compositions for promoting the healing of wounds or fibrotic disorders, in particular for promoting the healing of wounds or fibrotic disorders with reduced scarring.
By "wounds or fibrotic disorders" is meant any condition which may result in the formation of scar tissue. In particular, this includes the healing of skin wounds, the repair of tendon damage, the healing of crush injuries, the healing of eye wounds, including wounds to the cornea, the healing of central nervous system (CNS) injuries, conditions which result in the formation of scar tissue in the CNS, scar tissue formation resulting from strokes, and tissue adhesion, for example, as a result of injury or surgery (this may apply to e.g. tendon healing and abdominal strictures and adhesions). Examples of fibrotic disorders include pulmonary fibrosis, glomerulonephritis, cirrhosis of the liver, and proliferative vitreoretinopathy.
By "reduced scarring" is meant reduced level of scarring relative to an untreated wound or fibrotic disorder.
In particular, there is a lack of compositions for promoting the healing of wounds or fibrotic disorders with reduced scarring. Scar tissue formation, although providing mechanical strength to a healed wound, can be unsightly and may impair the function of the tissue.
This is particularly the case in wounds which result in scar tissue formation in the CNS, the scar tissue inhibiting the reconnection of severed or re-growing nerve ends. so significantly affecting their function.
Compositions for promoting the healing of wounds or fibrotic disorders may also be used together with compositions for use in the treatment of chronic wounds, for example venous ulcers, diabetic ulcers and bed sores (decubitus ulcers), especially in the elderly and wheel chair bound patients. Such compositions may be extremely useful in patients where wound healing is either slow or in whom the wound healing process has not yet started. Such compositions may be used to "kick-start" wound healing and may then be used in combination with the compositions of the present invention. Hence not only may a chronic wound be healed, but it may be healed with reduced scarring.
The activation of LTGF-.beta. (Latent Transforming Growth Factor-.beta.) to active TGF-.beta. is a critical step in the healing process. LTGF-.beta. (which comprises TGF-.beta. bound to the LAP (Latency Associated Peptide) which in turn may be bound to the LTBP (LTGF-.beta. Binding Protein)) binds to cell-surface M6P (mannose-6-phosphate) receptors via M6P-containing carbohydrates in the LAP (Purchio, M. F. et al., 1988, J. Biol. Chem., 263: 14211-14215; Dennis, P. A. and Rifkin, D. B., 1991, Proc. Natl. Acad. Sci. U.S.A., 88: 580-584; Shah, M. et al., 1992, Lancet, 339: 213-214; Shah, M. et al., 1994, J. Cell Sci., 107: 1137-1157). This binding allows the activation of the LTGF-.beta. a process also involving transglutaminase and plasminogen/plasmin.
Due to the binding of LTGF-.beta. to the M6P receptor, M6P itself may play a significant role in the healing process by competing with the M6P-containing carbohydrates in the LAP for the M6P receptor binding site. By increasing the quantity of M6P at a site (by "site" in this context is meant a site of wounding or a fibrotic disorder), the binding of LTGF-.beta. to the M6P receptor may be inhibited (or at least reduced), and the levels of fibrotic and non-fibrotic TGF-.beta. affected.
Although M6P is extremely useful, it is quickly metabolised and so previous attempts to increase the levels of M6P at a wound site have focused upon providing a constant supply of M6P to the wound site by the use of slow/sustained/biocompatible non-inflammatory delivery systems. Such slow/sustained delivery systems are both costly and inconvenient and are extremely difficult to produce since it is difficult to achieve slow release from a non-inflammatory/biocompatible vehicle.
The present inventor has found that, surprisingly, analogues of M6P may be used to promote the healing of wounds or fibrotic dis
REFERENCES:
patent: 4703040 (1987-10-01), Markov
Ferguson Mark William James
Freeman Sally
Moore Sarah Glenys
Peselev Elli
The Victoria University of Manchester
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