1. Field of the Invention
The present invention relates generally to methods and compositions for the enhancement of cellular proliferation and for the treatment of wounds and other disorders. More specifically, the invention relates to the use of neuropeptides for wound treatment in general and corneal wound treatment and vascular wound treatment in particular and, more particularly, to the use of Substance P and analogs and conjugates thereof for such wound treatment, wherein the neuropeptide is incorporated into a delivery vehicle that contains a polymeric delivery carrier that increases the dwell time of the neuropeptide, thereby reducing the number of administrations required when compared to administration of the neuropeptide alone.
2. Detailed Description of the Background Art
Traumatic injury and disease can cause damage to the skin, tissue, and body organs that requires cellular regeneration for healing. Accidental injuries such as cuts, abrasions, burns, and intentional surgical procedures result in wounds that can affect large areas of the skin or affected body organs and can require lengthy periods to heal. Long healing times are a particular problem with denervated regions of the extremities and with wounds on sensitive areas, such as corneal wounds and wounds on the bottom of the feet, buttocks and other weight bearing surfaces, which are difficult to treat over prolonged periods. For these reasons, it would be desirable to provide methods and pharmacological agents which can be used to promote rapid healing of wounds and other injuries to the skin, tissue, and body organs.
A variety of cellular growth promoting hormones have been identified that are capable of enhancing cellular proliferation, and these hormones have been used in the treatment of wounds. Exemplary growth promoting hormones include, but are not limited to, cytokines, lymphokines, interleukins, chemokines, epidermal growth factor, platelet-derived growth factor, insulin, insulin-like growth factor, transforming growth factor-β, nerve cell growth factor, fibroblast growth factor, platelet-derived growth factor, granulocyte-colony stimulating factor, granulocyte-macrophage colony stimulating factor, neurotropins, erythropoietin, thrombopoietin, myostatin, growth differentiating factor-9, hepatocyte growth factor, and the like. While use of these hormones continues to hold promise, no one growth promoting agent is known to be optimal for all situations. Thus, it would be desirable to identify additional substances and compositions which have therapeutic value as growth promoting agents, and it would be further desirable to identify substances and compositions which are capable of enhancing or modulating the effect of these and other growth promoting substances alone or in combination with other substances.
In addition to cellular proliferation, wound healing requires the elaboration of extracellular matrices and development of cellular attachment mechanisms in order to achieve normal tissue morphology. For example, the formation of fibronectin is an important function in normal wound healing. Without sufficient expression of fibronectin and other cellular matrix substances, regenerated tissue can have an abnormal morphology. Thus, it would be desirable to identify substances and compositions which could promote such additional wound healing responses.
U.S. Pat. No. 5,616,562, issued to Murphy et al. on Apr. 1, 1997 and expressly incorporated herein by reference in its entirety, discloses methods and compositions using Substance P to promote wound healing. The '562 patent discloses methods of healing a corneal or epithelial wound in a Substance P deficient patient, and such methods require multiple administrations of Substance P at frequent time intervals to treat the corneal or epithelial wound. Therefore, methods of treating corneal or epithelial wounds with a composition including Substance P that could increase the dwell time of the Substance P and thereby decrease the required number of administrations of the composition, are desired. In addition, methods of treating wounds other than corneal or epithelial wounds with Substance P are also desired.
For the above reasons, it is an object of the present invention to provide pharmacological agents and formulations useful for the topical treatment of wounds and other disorders. Desirably, the compositions will be capable of providing a potent mitogenic activity which enhances the proliferation of epithelial cells, fibroblasts, and the like. The compositions, in certain embodiments, should also be capable of stimulating the expression of extracellular matrices and development of cellular attachment mechanisms which contribute to normal morphology in the healed tissue. In one embodiment, the compositions should be capable of enhancing or modulating the growth promoting activity of other growth promotants. The compositions should be suitable for topical application to the skin and body organs, including the eye and skin, and should also be suitable for administration to treat vascular wounds. In addition, the compositions of the present invention should further be suitable for incorporation into a wide variety of delivery vehicles such as but not limited to, salves, lotions, creams which may or may not include such additional components as Aloe Vera, Oat Beta Glucan, Hyaluronic Acid and other large polymeric delivery carriers.