Surgery: splint – brace – or bandage – Bandage structure – Skin laceration or wound cover
Reexamination Certificate
2000-02-29
2003-09-30
Lewis, Kim M. (Department: 3761)
Surgery: splint, brace, or bandage
Bandage structure
Skin laceration or wound cover
Reexamination Certificate
active
06627785
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the application of sequestrants and inhibitors of protease to wounds for the purpose of enhanced healing. The invention also relates to the inclusion of these active agents in wound dressings to which they may be,either compositioned or bound by covalent or ionic means for the purpose of controlled release or sequestration.
2. Description of the Prior Art
A wound of the skin is any degradation of its normal structure and function resulting from an internal or external pathology. A healing wound has aspects relating to control of infection, resolution of inflammation, angiogenesis, regeneration of a functional connective tissue matrix, contraction, resurfacing, differentiation, and remodeling. Chronic wounds are wounds that don't heal in a timely process.
Chronic wounds represent a worldwide health problem. Chronic wounds are a growing health care problem largely due to increasing longevity of the American population. Pressure or decubitus ulcers which are a type of chronic wound represent an estimated 3% to 5% incidence in hospital patients. In patients with spinal chord injuries the incidence of chronic wounds is 25% to 85%. Approximately one million Americans hospitalized yearly will develop pressure sores resulting in a cost of 750 million dollars for patient care.
Elastase is perhaps the most destructive enzyme in the body and has been well characterized in non-healing wounds. An excessive concentration of both the serine protease elastase and matrix metalloproteinases (MMPs) in chronic non-healing wounds has been shown to deleteriously degrade cytokine growth factors, fibronectin, and endogenous levels of protease inhibitors necessary for healing. Although numerous studies with both animals and human beings have shown that growth factors may accelerate healing of chronic wounds, therapeutic attempts to modulate the wound healing response with them have had limited success.
The composition of the wound dressing is relevant to designing a mechanism-based approach to protease inhibition in the environment of the wound fluid. (Wiseman D M, Rovee, D T, Alvarez O M Wound dressing: design and use in Wound Healing Biochemical & Clinical Aspects, eds. Cohen I K, Diegelmann, R F, Lindbald, W J, 1992, Hartcourt Brace Jovanovich, Inc. 562-580). The fiber or gel composition of synthetic dressings, applied to chronic wounds, include synthetic hydrogel polymers, collagen, hydrocolloids, alginates and cotton and carboxymethylcellulose. Controlled release of agents linked with important roles in wound healing includes growth factors, antibiotics, and trace elements. The use of the enzyme inhibitor aprotinin for treatment of corneal ulcers was reported, however, there have been no known reports of treatment methods on the release of elastase inhibitors into wounds.
U.S. Pat. No. 5,098,417 to Yamazaki et al. teaches the ionic bonding of physiologically active agents to cellulosic wound dressings.
U.S. Pat. No. 4,453,939 to Zimmerman et al. teaches the inclusion of aprotonin in compositions for “sealing and healing” of wounds.
U.S. Pat. No. 5,807,555 to Bonte et al. teaches the inclusion of inhibitors for alpha-1-protease, collagenase, and elastase in pharmaceutical compositions for promotion of collagen synthesis.
U.S. Pat. No. 5,696,101 to Wu et al. teaches use of oxidized cellulose (e.g. oxycel) as a bactericide and hemostat in treatment of wounds.
World Patent WO 98/00180 to Watt et al. teaches complexation of oxidized cellulose with structural proteins (e.g. collagen) for chronic wound healing; and references the utility of oligosaccharide fragments produced by the breakdown of oxidized cellulose in vivo in the promotion of wound healing.
SUMMARY OF THE INVENTION
We have now discovered that direct application of protease inhibitors to wound sites promotes wound healing by amelioration of the deleterious effects of elastase on cytokines, endogenous anti-proteases, and fibronectin in the wound microenvironment. While not wanting to be bound thereto, it is Applicants' theory that the release of protease inhibitors into the chronic wound or modification of wound dressing fibers for selective protease sequestration may be beneficial in restoring the proteinase/antiproteinase balance needed to avoid degradation of growth factors and effectively accelerate healing of chronic wounds. The active agents are applied to the wound site in conjunction with known wound dressings, preferably polysaccharide based wound dressings. The invention includes methods of linking these protease inhibitors either covalently or ionically to wound dressings including polysaccharide containing matrices. Also described are formulations of the inhibitors onto fibers, the method of production of same, and pharmaceutical compositions which are effective in the treatment of mammalian chronic wounds.
Therefore, it is an object of this invention to provide methods and compositions for the enhanced treatment of mammalian wounds comprising the application of protease inhibitors.
Another object is to provide novel conjugates of protease inhibitors with wound dressings for use as sequestrants in wound environments.
A further object is to provide ionic systems for sustained release of protease inhibitors into the wound environment.
Other objects and advantages will become apparent from the ensuing description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based upon the previously unrecognized discovery that inhibitors and sequestrants of proteases may be used as healing accelerants of chronic wounds. These may be physically applied on wound dressings, or in the alternative may be ionically or covalently conjugated to a wound dressing material for purposes of sustained release of active agent or sequestration of endogenous constituents from the wound environment. The term protease inhibitor is meant to include those materials which effect a diminution in protease activity in the wound environment.
Specific pharmacological effects of elastase inhibitors and sequences associated with wound dressings include inhibition of the breakdown of growth factors that stimulate migration of cells to the ulcer site of the wound leading to the growth of new tissue that heals the open wound. This technology is broadly applicable to all forms of chronic wounds including diabetic ulcers and decubitus bedsores. Both peripheral and central administration of the compounds formulated on wound dressings accelerate wound healing of chronic wounds. The compounds of this invention may be applied to wound dressings as agents that may be released into the wound and thereby inhibit human elastase and thus prevent growth factor and tissue degradation. Alternatively the inhibitors of this invention are covalently bound to the wound dressing. As a component of such a matrix, they are able to sequester destructive elastase from the microenvironment of the wound, thus preventing the degradation of growth factors and fibronectin that would otherwise occur.
The therapeutic administration of the modified wound dressings containing inhibitors include a pharmacologically effective dose of the inhibitor or sequestrant when used in the treatment of a patient in need thereof. The dose of inhibitor or sequestrant required on the wound dressing to promote accelerated healing in the patient ranges from about 0.2 mg/gram fiber to about 200 mg/gram fiber per day, with this in turn being dependent upon specific factors including patient health, wound type, and specific-protease inhibitor/sequestrant utilized. The amount of active agent required can be readily determined by those skilled in the art.
The term patient used herein is taken to mean mammals such as sheep, horses, cattle, pigs, dogs, cats, rats, mice and primates, including humans.
The term wound dressing used herein is taken to include any pharmaceutically acceptable wound covering such as:
a) films, including those of a semipermeable or a semi-occlusive nature such as polyurethane copolymers, acrylamides, ac
Cohen I. Kelman
Diegelmann Robert F.
Edwards J. Vincent
Yager Dorne R.
Lewis Kim M.
Virginia Commwealth University
Whitham Curtis & Christofferson, P.C.
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