Conveyance of anti-infective activity to wound dressings

Details Conveyance of anti-infective activity to wound dressings Conveyance of anti-infective activity to wound dressings

2000-10-19

2003-07-15

Lankford, Jr., Leon B. (Department: 1651)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S445000, C424S094400, C424S667000, C424S669000

Reexamination Certificate

active

06592890

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compositions and devices for conferring to wound dressings anti-infective activity.
BACKGROUND OF THE INVENTION
Wound dressings absorb and draw off excess blood, serum and pus in maintaining a clean site conducive to healing. They also aid healing by controlling and restricting water loss. Too much retention of water over the wound site can result in maceration of the skin and impaired healing. Too much loss can lead to hypotherinia and severe electrolyte imbalances, especially in the case of burn patients. Materials used in the manufacture of wound dressings include woven fibers, porous foam pads, and cast hydrogels made up of cellulose and its derivatives (cellulosics), polyesters, nylon, polyacrylamides, polyurethanes, and collagen. The exudation of serum and blood from wounds to the external environment, and the difficulty in maintaining a sterile site, can lead to serious infection because this rich medium when trapped in wound dressings which also maintain a moist environment provides an opportune site for bacterial growth. The definition of a wound dressing as used in this context includes dressings designed to cover compromised skin including tears to the skin caused by blunt trauma, burns, punctures, ulcerations of the skin in which an exudate occurs, etc.
Other conditions at the wound site also occur which promote bacterial growth. First, the bicarbonate buffer system of blood depends upon the dissolution of gaseous carbon dioxide into blood, and its hydration to carbonic acid (catalyzed by carbonic anhydrase present in great abundance in red blood cells) in balancing the blood pH. The equilibrium between the gaseous form of carbon dioxide and bicarbonate lies several thousand fold in favor of the gaseous form of carbon dioxide. In an open wound carbon dioxide is rapidly lost to the atmosphere. This loss of carbon dioxide drives the wound site toward a more alkaline environment, a condition favorable to bacterial growth. Second, the oxygen tension drops precipitously as a consequence of bacterial growth, tissue metabolism, the loss of vascularization and adequate perfusion, and the poor solubility of oxygen across the aqueous interface of the wound site. This is further aggravated by the diffusion barrier of wound dressing materials which restrict free exchange of oxygen. Since the body's phagocytic defense system requires oxygen to generate an anti-infective defense (Klebanoff, S. J. and Clark, R. A. (1978) in
The Neutrophil: Function and Clinical Disorders
, North-Holland Publishing Company, Amsterdam), the decreased availability of oxygen impedes phagocytic killing reactions which otherwise help ward off infections. Although studies show there is an overall drop in the pH of fluid within wound sites by about a half pH unit below the normal blood pH within hours of application of a wound dressing, about a two-fold increase in dissolved carbon dioxide above normal blood levels, and a precipitous drop in oxygen tensions by 10 to 20 fold below that found in normal blood (Ninikoski, J., Heughan, C. and Hunt, T. K. (1971)
Surgery, Gynecology
&
Obstetrics
133: 1003-1007; Varghese, M. C. et al. (1986)
Arch Dermatol
122: 52-57; Katz, S., McGinley, K. and Leyden, J. J. (1986)
Arch Dermatol
122: 58-62; Sirvio, L. M. and Grussing, D. M. (1989)
J Invest Dermatol
93: 528-531), this is the result of two opposing reactions: (i) an initial loss of dissolved carbon dioxide from the wound site concomitant with alkalinization of the wound which promotes conditions conducive to bacterial growth and infection; and (ii) a subsequent sharp fall in oxygen tension concomitant with bacterial propagation and tissue respiration coupled with the poor diffusibility of oxygen across the air-water interface of the wound site. Lactic acidosis also ensues. In deep wounds these conditions can create serious, pus loaded abscesses infected with anaerobic bacteria requiring surgery and drainage. In some instances, without proper infection control, life-threatening septicemia may ensue.
Iodine is a potent anti-infective agent with much promise as an affective agent in preventing infections associated with wound care. It has been used for over 150 years in various formulations as a sterilizing agent. Examples include tincture of iodine (an alcoholic solution of free iodine and inorganic iodide), Lugol's solution (a strong mixture of aqueous inorganic iodide and iodine), and in varying complexed forms of elemental iodine using water-soluble iodophors such as polyvinylpyrrolidone (Povidone-iodine) or iodine-bound cadexomers (biodegradable carbohydrate polymer complexes mixed together with elemental iodine formulated in polyethylene glycol). Iodine exists in several oxidation states including its fully reduced iodide (I—) state in addition to its oxidized diatomic free elemental state (I
2
), and in several higher oxidation states in combination with oxygen (e.g., hypoiodate (IO—), iodate (IO
3
—) and periodate (IO
4
—)). In aqueous solutions iodide forms an equilibrium complex with elemental iodine, yielding soluble tri-iodide (I
3
—), a bound form of iodine devoid of microbicidal activity. Several studies have shown that it is the free form of iodine which exhibits microbicidal activity.
Iodine is difficult to handle in the free form, however, because it is chemically reactive with a number of substances in, and outside, of the body. It is also volatile and readily escapes into the atmosphere. Methods of trapping it in a semistable form involve complexation as an iodophor (e.g. complexed forms of elemental iodine in solution using specific organic binding agents). Among the better known iodofors is Povidone-Iodine, also known as Betadine®, a water soluble polyvinylpyrrolidone organic polymer mixed with inorganic iodide and elemental iodine. In this formulation most of the elemental iodine present binds to the hydrophobic polyvinylpyrrolidone backbone as well as to the cationic pyrrole nitrogen in the form of a tri-iodide complex, none of which forms exhibit any microbicidal activity.
Free elemental iodine is only a small fraction of the total iodine in Povidone-Iodine. 10% Povidone-Iodine, for example, is formulated at ~1% total “available” iodine (e.g., 10,000 ppm). Its free elemental iodine concentration varies from ~0.8 to 1.2 ppm (
Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning
, 2
nd
edition). LeVeen et al. (
Surgery, Gynecology
&
Obstetrics
176:183-190, 1993) have pointed out several deficiencies in Povidone-Iodine formulations for the treatment of wounds including low free elemental iodine levels of marginal efficiency as an anti-infective. They noted that the low level of free iodine is ineffective except against extremely sensitive bacteria. Polyvinylpyrrolidone also contaminates the wound site and has been noted to cause granulomas in wounds. LeVeen et al., and later Shikani and Domb (
J. Amer. College of Surgeons
183:195-200, 1996), sought to get around these problems by dissolving elemental iodine into polyurethane, a water insoluble polymer with iodine binding properties. Various iodine loaded polyurethane patches have evolved through this approach (U.S. Pat. No. 5,762,638). Iodine impregnated polyurethane dressings are not easily produced with uniform and predictable levels of free iodine, however, as it is difficult to control retention of iodine in a polyurethane polymer base. Iodine trapped in this manner not only diffuses free of the polymer base creating problems regarding shelf-life storage and handling of the wound dressing material, but it is also reactive and can be consumed before it comes into contact with wound fluid.
Alternative approaches for sequestering free iodine have included its complexation in biodegradable carbohydrate polymeric hydrogels (U.S. Pat. No. 4,783,448; U.S. Pat. No. 4,010,259). In the latter hydrogel formulations, the iodine content is stated to preferably range from a low of about 0.4% to about 2% (wet weight of gel). These formulations are un

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