Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-01-28
2002-10-01
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S443000, C424S444000, C424S445000, C424S447000, C424S448000, C424S426000, C424S428000, C424S484000
Reexamination Certificate
active
06458386
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to wound dressing materials comprising either cross-linked methacrylamide modified gelatin, or co-polymerized methacrylamide modified gelatin with vinyl-substituted polysaccharides, or cross-linked vinyl-substituted polysaccharides and gelatin being physically entrapped in a semi-interpenetrating network. The material is useful for the covering of a variety of wound types, particularly chronic wounds and burns. The material is also suitable for the controlled release of drugs. When loaded with suitable growth factors or wound repair promoting substances, the matrix is useful for the fabrication of wound dressings for the treatment of a variety of wound and burns.
BACKGROUND OF THE INVENTION
A very large number of people are suffering from chronic non-healing skin wounds. A common feature in the treatment of these wounds is that they need covering for optimal healing. The beneficial effect of covering wounds is situated at different levels and is dependent on the type of dressing material used. For acute wounds, suitable dressings may help to achieve haemostasis and thus control blood loss. Also, covering of wounds effectively shields the wound from the environment, thus protecting it from microbial contamination. Furthermore, some so-called occlusive or semi-occlusive wound dressings have the capability of maintaining the wound moist, which is beneficial for healing. Finally, some wound dressings may themselves directly promote the healing process, for instance because they contain components which directly promote cell growth or migration or which attract or activate cells from the immune system which themselves secrete growth-promoting substances. Other dressings may contain antimicrobial substances, which are helpful to control infection of the wound.
Over time, a surprisingly wide variety of dressing materials have been used for wound covering, many of which are currently commercially available. Each of them has its own indications, dependent on wound type, depth, size, absence or presence of infection, level of exudate formation, etc.
Cotton gauze, for instance, is widely used as wound dressing. It has the advantage of being cheap, but the disadvantage of being not occlusive and sometimes becoming encrusted into the wound. To prevent this, these dressings are sometimes impregnated with a greasy substance, such as paraffin. A commercially available example of such a dressing is Jelonet™ (Smith and Nephew, UK).
Another class of wound dressings are the absorptive hydrogel dressings. These have a high capacity for the absorption of wound exudate. They consist of hydrophilic polymers such as gelatin, polysaccharides, polyacrylamide, etc, which swell upon contact with wound fluid and can absorb several times their own weight of exudate. Commercially available hydrogel dressings include Intrasite gel (Smith and Nephew, UK) and Vigilon (CR Bard, USA). A special type of hydrogels are the alginates, which are hydrophilic polysaccharides extracted from seaweed. They are produced as thin non-woven tissues or as ropes. Upon contact with the wound fluid, they turn into a gel which has a high absorptive capacity for wound fluid. Examples include Kaltostat (Brit-Cair, UK) and Sorbsan (Steriseal, UK).
Another type of dressings are the occlusive or semi-occlusive dressings. In their simplest form, they usually exist of a thin, flexible plastic membrane, e.g. from polyurethane. To facilitate application, these dressings are usually fabricated with a self-adhesive coating. These dressings are called occlusive because they limit water evaporation from the wound surface, thus keeping it moist. Examples of such dressings are Opsite (Smith and Nephew, UK) and Tegaderm (3M, USA). Examples of semi-occlusive dressings are Omiderm (Iatro Medical Systems, UK) and Exkin (Koninklijke Utermöhlen, The Netherlands). The latter dressings allow a slightly higher evaporation rate, resulting in a semi-dry wound surface.
A more complex type of occlusive dressings are the hydrocolloid (HCD) dressings. These are made up of hydrocolloid particles (e.g. consisting of gelatin, pectin, carboxymethyl cellulose, etc) embedded in a hydrophobic matrix (e.g. a polyisobutylene, styrene-isoprene-styrene copolymer). These dressings may be backed with an occlusive membrane and/or a foam plastic layer. In addition to being occlusive, HCD dressings have a high absorptive capacity, making them very suitable for the treatment of wounds producing high amounts of exudate. These beneficial properties have made HCD dressings among the most successfully used dressings for the treatment of chronic ulcerations of the skin. Commercially available examples of these dressings include DuoDERM© (Convatec, UK), Tegasorb™ (3M, USA), and Comfeel Coloplast, Denmark)
Although highly successfull recent reports suggest that HCD dressings may nevertheless induce undesirable side reactions in the treated tissues. For example, Van Luyn reports that DuoDERM (Convatec, UK), Biofilm (Biotrol SPA, France), Comfeel (Coloplast, Denmark) and Ulcer dressing (Johnson and Johnson, USA), all of which are HCD dressings, fall within the high toxicity class when tested in a methylcellulose assays using human skin fibroblasts as target cells (Van Luyn, M. Doctoral Thesis, 1992, State University Groningen, The Netherlands; Van Luyn, M., Abstract Book of the joint WHS/ETRS meeting, Amsterdam, 1993 p114). All the HCD dressings tested by this author highly inhibited cell growth (>70%) and induced strongly deviant morphologies in the surviving cells. Leek et al. (Abstract Book of the Second Annual WHS Meeting, Richmond, Va., USA, p75, 1992) have tested four HCD dressings in full-thickness excisional wounds in pigs. All dressings induced development of granulomatous lesions between 4 and 10 days post wounding and exhibiting little evidence of resolution at 3 months post wounding. The most severe reaction was obtained with DuoDERM and Intrasite HCD. Rosdy and Clauss (J. Biomedical Mat. Res. 24, 363-3777, 1990) found that the HCD dressing Granuflex™ (Bristol-Myers Squibb, USA) induced cytopathic effects on MRC5 fibroblasts and epidermal cells upon direct contact. Young et al. (J. Invest. Dermatol. 97, 586-592, 1991) describe in an animal model system the development of deep-seated foreign body type reactions and granulomata in healed wounds which were treated with HCD dressings. Our own experiments with the HCD dressing DuoDERM™ show that this dressing results in a marked and chronic inflammatory response when placed in full thickness wounds in pigs.
The above mentioned data suggest that, while HCD dressings may promote wound healing in the short term, their use is often associated with undesirable inflammatory effects. Therefore, it is clear that there is a need for a wound dressing displaying the beneficial properties of HCD dressings, yet resuking in substantially less chronic inflammation or foreign body response. Such a wound dressing would stimulate granulation tissue formation, be absorptive and eventually be biodegradable within a limited time frame.
Gelatin, which is a denatured form of the protein collagen, has been used in a variety of wound dressings and controlled release systems. Because of their relative low melting point, gelatin gels are not very stable at body temperature. Consequently, it is necessary to stabilize these gelatin gels before they can be used for wound healing purposes. This is usually done by establishing cross-links between the protein chains by treating gelatin with either formaldehyde or glutaraldehyde. Alternatively, this can be accomplished by cross-liming of gelatin with polyaldehydes produced by partial oxidation of polysaccharides such as dextran (Schacht E H, Nobels M, Vanteenkiste S, Demeester J, Fransen J, Lemahieu A. Polym Gels Networks 1993; 1: 213-224). Cross-linked gelatin may be fabricated into dry sponges which are useful for inducing haemostasis in bleeding wounds. Commercially available examples of such sponges include Spongostan® (Ferrosan, Denmark) and Gelfoam (U
Delaey Bernard
Draye Jean-Pierre
Schacht Etienne
Van Den Bulcke An
Channavajjala Lakshmi
Howrey Simon Arnold & White , LLP
Innogenetics N.V.
Page Thurman K.
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