Compositions and methods for promoting wound healing

Details Compositions and methods for promoting wound healing Compositions and methods for promoting wound healing

2001-03-30

2003-06-24

Russel, Jeffrey E. (Department: 1654)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Biocides; animal or insect repellents or attractants

C106S015050, C424S443000, C424S487000, C424S618000, C514S003100, C514S004300, C602S048000, C602S050000, C604S020000, C604S304000, C604S307000, C607S050000

Reexamination Certificate

active

06582713

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to methods and compositions for promoting wound healing. In particular, the invention provides cyanoacrylate polymer sealants in combination with biologically active agents including silver and insulin.
BACKGROUND OF THE INVENTION
Normal wound healing involves the complex orchestration of a series of interrelated cellular events and cytokine cascades (Pierce, G. F. and Mustoe, T. A., Ann. Rev. Med., 46:467-481 (1995); and Martin, P., Science, 276:75-81 (1997)). The principle phases of wound healing consist of formation of a fibrin clot, followed by infiltration with inflammatory cells and fibroblasts, generation of granulation tissue and angiogenesis, wound contraction, and re-epithelialization. Growth factors and cytokines are supplied first by degranulating platelets, and later by fibroblasts and inflammatory cells, principally neutrophils and macrophages. The inflammatory response plays an active part in wound healing. If macrophage infiltration is prevented, wound healing is seriously impaired.
Currently, there are numerous methods and compositions available to treat wounds and to promote wound healing. A wound may constitute a variety of insults or damage to external body tissues, for example, a wound may involve a laceration, cut or scrape, surgical incision, sore, thermal burn, puncture, or decubitus ulcer, e.g., bed sores. Wounds can be classified in one of two general categories, partial thickness wounds or full thickness wounds. A partial thickness wound is limited to the epidermis and superficial dermis with no damage to the dermal blood vessels. A full thickness wound involves loss of the dermis and extends to deeper tissue layers and involves disruption of the dermal blood vessels. The healing of the partial thickness wound occurs by simple regeneration of epithelial tissue. Wound healing in full thickness wounds is more complex, involves multiple cell types (Martin, Science, 276:75-81 (1997)), and three stages. The first stage involves an immediate inflammatory response (2-5 days post wounding), followed by a proliferative phase (2 days-3 weeks) where no blood vessels (angiogenesis) and collagen are generated in the wound bed, resulting in the formation of granulation tissue. Contraction and re-epithelialization of the wound also occur during this phase. Finally, a maturation phase occurs during which collagen in the wound is subject to turnover and remodeling, ultimately resulting in the formation of scar tissue.
Intact epidermis serves as a mechanical barrier to infection. Due to the extensive tissue loss or damage in full thickness wounds, infection of more likely than in partial thickness injuries. Not properly cleaned and treated, a full thickness wound may, in severe cases, result in the development of a life-threatening infection.
A large number of dressings, bandages, and topic medicaments are available for the treatment of wounds. These products fall into two categories, passive and active. Passive wound dressings are dressing which serve only to provide mechanical protection and a barrier to infection. The dressings themselves do not supply any composition which enables or facilitates the healing process of the wound. Examples of passive dressings include gauze and adhesive bandages. Active dressings are dressing which supply some biologically active compound to the site of a wound. One type of active dressing is a dressing or wrapping which delivers or has been impregnated with antimicrobials (e.g., Bacitracin).
Another family of dressings which contain both passive and active properties are the hydrogels or hydrocolloids. Although many of these dressings do not supply any biologically active compound to the wound, they are specifically designed to create a moist environment around the wound to promote wound healing. Hydrogel and hydrocolloid dressings have been formulated to antimicrobials to help prevent and/or treat infection. However, to date, hydrogels or hydrocolloids have not been formulated with components that actively promote wound healing.
It has been suggested that the topical application of biological compounds may play an active role in wound healing. These compounds include mitogens, cytokines, growth factors, and hormones (e.g., PDGF, EGF, &bgr;-FGF, GM-CSF, IGF-I, TGF-&agr;, and TGF-&bgr;). However, there are limitations to these therapies. First, it is difficult to regulate the dosage of such an application. A liquid or viscous paste containing these components applied to a wound will tend to spread away from the site of the wound, or will be absorbed by and removed from the wound by dressings which are placed over the wound. Dressings which come in contact with the wound surface may also interfere with the normal healing process. Furthermore, these compounds are all polypeptides, they are extremely susceptible to rapid degradation following there application. Such degradation can occur from the contact of the polypeptides with proteases produced by bacteria normally on the surface of the skin. In addition, these agents may lack specificity in there action, and have adverse pleiotropic effects on adjacent tissues other than those tissues involved in wound healing.
In some cases, abnormal wound healing represents a significant health risk to patients. In particular, diabetic patients often experience slow and/or incomplete wound healing that may result in other serious consequences. Diabetes mellitus (DM) is a metabolic disease resulting from defective glucose utilization. A variety of molecular defects are implicated in the manifestation of type-I and type-II diabetes, including errors in insulin production, glucose transport, and glucose metabolism (Nathan, Scientific American Medicine (Dale and Federman, EDS.), Chapter 9, Section VI (1997)). Both type-I and type-II DM produce a variety of debilitating and life threatening complications, including degeneration of large and small blood vessels (i.e., macrovascular and microvascular disease) and increased susceptibility to infection. These two complications, unfortunately, make the DM patient prone to poor wound healing and wound infections. In extreme cases, limb amputation is necessary due to circulatory problems and infection at the site of wounds.
It has been proposed that insulin can be administered systemically or topically to help promote wound healing in diabetic and normal patients. The results described in the literature have been fairly inconsistent. Some studies have found that the topical application of insulin helps to promote wound healing (Hanam et al., The Journal of Foot Surgery, 22:298-301 (1983)) and others have found no significant effect by insulin on the rate of wound healing, particularly in decubitus ulcers (Gerber and VanOrt, Nursing Research, 28:16-19 (1979)). Two U.S. Pat. Nos. 5,145,679 and 5,591,709 have described the topical administration of insulin to a wound to promote wound healing. Both of these patents, however, describe the use of insulin in combination with glucose because the function of the insulin is to enhance the uptake of glucose and to thus promote wound healing.
SUMMARY OF THE INVENTION
The invention provides improved methods and compositions for promoting wound healing. In particular, the invention involves the use of cyanoacrylate polymer sealants in combination with therapeutics, such as silver and insulin, and related compositions. Cyanoacrylate polymers have previously been used to form sealants to close holes in tissue, or to replace or supplement sutures or as a hemostat. The cyanoacrylate can be applied to the skin as a liquid or gel to produce a protective barrier film. Although the prior art has suggested the use of cyanoacrylates alone, or sometimes in combination with antimicrobials (U.S. Pat. No. 6,001,345) the prior art has been limited. Prior patents have shown that most medications alter the performance of cyanoacrylates, either preventing them from setting or causing them to set so rapidly that they cannot be used to form protective films, see e.g. U.S. Pat. No. 5,684,042. Addi

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