Methods for treatment of wounds using time release compositions - Patents

Methods for treatment of wounds using time release compositions

Agent: O'melveny & Myers LLP - Newport Beach, CA, US
Inventors: Xaverius F. Walboomers, Matthias Hoekstra, J. A. Jansen
Class: 424423000 (USPTO)
#20060105017
05/18/06
A method for treatment of wounds associated with the insertion of a medical implant, wherein an inorganic therapeutic agent containing potassium, rubidium, calcium and zinc cations is applied to the wound site on a silicone or bioabsorbable membrane. The therapeutic composition is provided in a long lasting, timed delivery formulation to improve the efficacy of the therapeutic agent. The membrane may contain a micro-texture to further control delivery of the therapeutic agent to the wound site.
FIELD OF THE INVENTION
[0002] This invention relates to the treatment of wounds, particularly wounds associated with medical implants which resist healing and thereby negatively interfere with the implant acceptance. It further relates to the use of timed release formulations of synthetic compositions containing the key ingredients of aqueous oak bark extract delivered on silicone or bioabsorbable membranes as an aid in the establishment and/or control over the chemical environment associated with extra cellular matrices.
SUMMARY OF THE INVENTION
[0006] Various authors already described an imbalance of matrix metalloproteinases (MMPs), and of MMP inhibitors, in chronic wound tissue and -fluid. It is assumed that PHI-5 has the capability to correct such imbalance between MMPs and MMP-inhibitors. Previously, many studies have shown comparable inhibition of several proteinases by zinc and other divalent metal ions (copper, cadmium, nickel, calcium) from a variety of chemical and organic sources. It has now been found that microtextured silicone wound covers loaded with PHI-5 can improve wound healing, when placed in a standardized full-thickness cutaneous wound in vivo. Through studies of the efficacy of PHI-5 in a standardized animal model, it has been discovered that delivering the PHI-5 composition to the wound site via silicone wound covers significantly improves the initial efficacy of wound healing.
[0007] Standardized studies were performed on guinea pigs having identical full thickness cutaneous wounds, wherein the wounds were treated with varying initial concentrations of PHI-5 delivered on a silicone substrate implanted in the wound site. The results showed a significant decrease in wound size in the first week healing corresponding to the concentration of PHI-5 delivered. Subsequent analysis at three and six weeks showed that no significant differences in the wound size between wounds. These initial results were achieved without use of a sustained release formula of PHI-5, thus it is believed that the significant initial increase in efficacy of the wound healing was a result of the initial week long application of the silicone impregnated wound cover. Addition of an extended, slow release carrier to the PHI-5 loaded onto a micro-textured silicone pad or bioabsorbable implant will further improve the efficacy of wound healing. Any sustained release carriers or methods for sustained release known in the art may be used in combination with the PHI-5 to achieve varying periods of release for the PHI-5 ions and thereby improve the efficacy of PHI-5 in treating chronic wounds, including without limitation: combination with microparticles, collagen or the salts of growth factors, encapsulation in biodegradable microsphere formulations, combination with films or sustained release foams.
[0008] For example, in an embodiment, PHI-5 may be combined with biodegradable polyester homopolymers, such as polyglycolide, polyactide, and poly(DL-lactide-co-glycolide), before being loaded on the micro-textured silicone pad to further extend the release time period of the PHI-5. Here, the polymers degrade with exposure to aqueous environments, such as biological fluids, until the polymer device loses its mechanical integrity, thereby releasing the micro-encapsulated PHI-5 formulation. Degradation rates of the polymers, and therefore delivery rate of the encapsulated PHI-5 formulation, may be varied with the type of polymer used and specific composition of the polymer.
[0009] Alternatively, a collagen delivery system may incorporate the PHI-5 ions into bioabsorbable collagen pads and then as the collagen is biosorbed at the wound site, the ions will be delivered. In an alternative embodiment, the PHI-5 may be loaded directly onto nanospun fibers and collagen pads. In another alternative embodiment, a multilayered system incorporating foams that will slow down the migration of the ions into the implant bed.
[0010] In an alternative embodiment, the PHI-5 formulation may be combined using salts of growth factors. Systems for the growth factors themselves have been developed for use with time release systems including PLGA delivery and liposomal delivery. Here, the same system would be used with the salts of growth factors. In an alternate embodiment, the PHI salts may be delivered via liposomal delivery. In this embodiment, the PHI-5 salts may be encapsulated in a non-polar delivery system.
[0011] For superficial wounds, it is further believed multiple applications of impregnated silicone pads containing a sustained release formulation of PHI-5 may further improve the efficacy of wound healing. Additionally, for subcutaneous wounds associated with the insertion of a medical implant, for example, a dental implant, the PHI-5 impregnated membranes of the present invention wherein the PHI-5 is contained within a timed release formulation may be particularly advantageous by providing for continuous delivery of the PHI-5 formulation to the wound site over varying time periods. In addition, the PHI-5 impregnated pads may be useful in other applications treatment of stage 1V decubitus ulcers.
Complete article is available online.