The early studies on the treatment of wounds have laid emphasis on a close examination of the functions of the cell stage, i.e., the functions of inflammatory cell and platelet [Allgower M. and Hulliger L., Surgery, 47, 603 (1960); Dicoreto P. E. and Browen-Pope D. F., Proc. Natl. Acad. Sci. USA, 80, 1919 (1983); and Houck J. C. et al., Biochem. Pharmacol., 17, 2081 (1968)].
Recently, growth factors to promote tissue growth have been used in the treatment of wounds such as chronic ulcers. The growth factors stimulate mitogenesis, which is the proliferation of cells such as fibroblast. The growth factors also stimulate angiogenesis, resulting in the ingrowth of new blood vessels. Moreover, the synthesis of collagen and extracellular matrix proteins is stimulated by the growth factors (L. Greenhalgh, J. Trauma 41:159 (1996)).
Cytokines have been found as growth factors associated with wound healing. Representative examples of such cytokines include basic fibrogrowth factor which is produced by keratinocytes and fibroblasts and promotes the growth of epithelial cells; platelet-derived growth factor (PDGF) which is produced by platelets and the endothelium and other cell types and promotes the abnormal proliferation of epithelial cells in association with epidermal growth factor (EGF); transforming growth factor-β (TGF-β) which is produced by fibroblasts and platelet and promotes the growth of connective tissue; epithelial cell-growth factor which is generated in salivary glands-stimulatory glands and promotes the proliferation of epithelial cells; fibroblast growth factor (FGF); and interleukin-1 which is produced by macrophages and epithelial cells and promotes the growth and mobility of epithelial cells. Becaplermin is a genetically engineered recombinant PDGF that is commercially available as an agent for the treatment of wounds in topical formulations by Johnson & Johnson under the trade name of Regranex®. EP 0 575 484 B1 discloses a pharmaceutical composition for the regeneration and repair of mammalian tissues which includes PDGF and dexamethasone. U.S. Pat. No. 5,981,606 discloses a pharmaceutical composition for treating wounds which includes TGF-β. WO 96/30038 discloses a pharmaceutical composition for wound healing which includes TGF-β and fibric acid together with antioxidants. U.S. Pat. No. 5,183,805 discloses a pharmaceutical composition having the effect of the regeneration of tissues which includes EGF. Japanese Patent No. 05070365 and U.S. Pat. No. 6,165,978 disclose wound healing formulation containing FGF.
Formulations utilizing hyaluronic acid as an active agent have also been reported as being useful in the treatment of skin ulcers (See U.S. Pat. No. 5,897,880). Formulations including sodium hyaluronate are marketed by LAM Pharmaceutical Corporation under the trade name of IPN Wound Gel®.
Topically applied fibronectin (glycoprotein found in blood plasma) has also been reported as being useful for increasing the rate of wound healing in corneal wounds (Nishida, Larch Opthalmology 101:1046 (1983)) and leg ulcers (Wysocki et al., Arch. Dermatol. 124:175 (1988)).
Although such treatments provide some patients with partial wound relief, they need long healing time and fail to exhibit optimum response to the treatment. As wounds, especially, chronic skin ulcers, become serious clinical problems, much effort has been made in finding effective treatments of the wounds. The underlying causes responsible for poor wound closure are complex and still poorly understood.
Therefore, it would be desirable to develop new and improved methods of treating wounds. Use of the present formulations either alone or in combination with various known therapeutic agents overcomes the limitations of the prior art.