US 2005O220837A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0220837 A1 Disegi et al. (43) Pub. Date: Oct. 6, 2005 (54) ANTIMICROBIAL HYALURONIC ACID Related U.S. Application Data COATINGS FOR ORTHOPEDIC IMPLANTS (60) Provisional application No. 60/506,760, filed on Sep. (76) Inventors: John Arthur Disegi, Reading, PA (US); 30, 2003. Robert Geoffrey Richards, Davos Dorf (CH); Llinos Gwawr Harris, Davos Publication Classification Platz (CH) (51) Int. Cl. .............................. A61F 2/28: A61F 13/00 Correspondence Address: (52) U.S. Cl. ......................................... 424/423; 623/16.11 JONES DAY 222 EAST 41ST ST NEW YORK, NY 10017 (US) (57) ABSTRACT (21)21) AppAppl. No.: 10/955,7771955, The invention relates to an implantp wherein the Surface of the implant is coated with hyaluronic acid or a derivative (22) Filed: Sep. 30, 2004 thereof. The coated implants resist microbial growth. Patent Application Publication Oct. 6, 2005 Sheet 1 of 5 US 2005/0220837 A1 FIGURE 1A FIGURE 1B FIGURE 1G TSS THY TG TF TAST FIGURE 1D FIGURE 1E FIGURE 1F FIGURE 2A FIGURE 2B Patent Application Publication Oct. 6, 2005 Sheet 2 of 5 US 2005/0220837 A1 TS TC FIGURE 3A FIGURE 3B FIGURE 4A FIGURE 4B CAC - 48 hours CP - 48 hours CPC - 48 hours FIGURE 4C FIGURE 4D Patent Application Publication Oct. 6, 2005 Sheet 3 of 5 US 2005/0220837 A1 FIGURE 5A FIGURE SB CP - 48 hours CP-96 hours FIGURE 5C FIGURE 5D FIGURE 6A FIGURE 6B CAC-96 hours - CPC-96 hours FIGURE 6C FIGURE 6D Patent Application Publication Oct. 6, 2005 Sheet 4 of 5 US 2005/0220837 A1 CC - 48 hours CC-96 hours R IO N s g 2 ra CH-48 hours CH-96 hours . s s g l CHP-96 hours CHR - 48 hours CHR-96 hours Patent Application Publication Oct. 6, 2005 Sheet 5 of 5 US 2005/0220837 A1 CHC - 48 hours CHC - 96 hours FIGURE 8A FIGURE 8B US 2005/0220837 A1 Oct. 6, 2005 ANTIMICROBAL. HYALURONIC ACID et al., ASAIO J. 141(3): M365-8 (1995); and Xiao in COATINGS FOR ORTHOPEDIC IMPLANTS Titanium in Medicine 417-449 (Springer-Verlag, Heidelberg 0001) This application claims the benefit of U.S. Provi and Berlin, 2001)). sional Patent Application No. 60/506,760, filed Sep. 30, 0007 Hydrophilic coatings, such as hyaluronan, are 2003, the entire disclosure of which is incorporated herein reported to have anti-adhesive properties. For example, by reference. Pavesio et al., Med. Device Technol. 8(7): 20-1 and 24-7 (1997) and Cassinelli et al., J. Biomater. Sci. Polym. Ed. FIELD OF THE INVENTION 11(9): 961-77 (2000) describe coated polymeric medical devices (e.g., intraocular lenses, Stents and catheters) with 0002 The invention relates to an implant wherein the decreased fibroblast and Staphylococcus epidermidis adhe Surface of the implant is coated with hyaluronic acid or a SO. derivative thereof. The coated implants resist microbial growth. 0008 U.S. Pat. No. 4,500,676 to Balazs et al. describes polymeric materials and articles made therefrom that are BACKGROUND OF THE INVENTION rendered biocompatible by including hyaluronic acid or a salt thereof with the polymeric material 0003. Once biomaterial implants are implanted in a body 0009 U.S. Pat. No. 4,853,225 to Wahlig et al. describes they are coated thereafter with host plasma constituents, an implantable medicament depot containing physiologi including protein components of the extracellular matrix cally acceptable excipients and at least one delayed release (ECM) such as fibrin; and eventually host cells-leading to active compound which is a chemotherapeutic of the gyrase the formation of Soft and hard tissue (see Baier et al., J. Biomed. Mater. Res. 18:337-355 (1984)). The ability of inhibitor type. Staphylococcus aureus (S. aureus) and StaphylococcuS epi 0010 U.S. Pat. No. 5,166,331 to della Valle et al., U.S. dermidis (S. epedermis) to adhere to the extracellular matrix Pat. No. 5,442,053 to della Valle et al., and U.S. Pat. No. and plasma proteins deposited on biomaterials is a signifi 5,631,241 to della Valle et al. all describe pharmaceutically cant factor in the pathogenesis of orthopaedic-device related useful fractions of hyaluronic acid for various applications, infections, and the resultant bacteria is reported to form i.e., between 50,000 and 100,000 Daltons which is useful for Biofilms (see Hoyle et al., Prog. Drug Res. 37.91-105 wound healing, and between 500,000 and 730,000 Daltons (1991)). which is useful for intraocular and intraarticular injections. 0004 Biofilm formation is a two-step process that The hyaluronic acid in these references may be present as requires the adhesion of bacteria to a Surface followed by free acid, as an alkali or alkaline earth metal Salt, or as a Salt cell-cell adhesion, forming multiple layers of the bacteria with one or more pharmacologically active Substances. (see, e.g., Cramton et. al., Infect. Immun, 67: 5427-5433 0.011 U.S. Pat. No. 5,505,945 to Gristina et al., U.S. Pat. (1999)). Once a biofilm has formed, it is difficult to clinically No. 5,530,102 to Gristina et al., U.S. Pat. No. 5,707,627 to treat because the bacteria in the interior of the biofilm are Gristina et al., and U.S. Pat. No. 5,718,899 to Gristina et al., protected from both phagocytosis and antibiotics (see as well as International Publication No. WO 94/15640, all Hoyle). Over the last decade, systemic antibiotics have not describe compositions containing a high concentration of provided an effective treatment against infections associated immunoglobulins IgA, IgG, and IgM to combat infections with implants (see, e.g., Petty et. al., J. Bone Joint Surg. 67: from microorganisms and viruses. The immunoglobulins in 1236-1244 (1985); Barth et al., Biomat. 10:325-328 (1989); these references can be immobilized on a variety of bio Wassall et al., J. Biomed. Mater. Res. 36(3): 325-330 (1997); compatible materials Such as collagen, fibrin, hyaluronan, and Lowy, N. Engl. J. Med. 339(8): 520-32 (1988)). biodegradable polymers, and fragments thereof. 0005 Hallab et al., Tissue Eng. 7(1):55-71 (2001); and 0012 U.S. Pat. No. 5,929,048 to Falk et al., U.S. Pat. No. Lange et al., Biomol. Eng. 19:255-61 (2002) report that 5,985,850 to Falk et al., and U.S. Pat. No. 6,069,135 to Falk Surface properties of medical implants, including topogra et al. all describe compositions, dosages, and methods for phy and chemistry are important in the promotion or inhi treating underperfused and pathological tissues containing a bition of cell and bacterial adhesion. Hence, various Studies therapeutic amount of hyaluronic acid and/or a Salt thereof have modified implant Surfaces in an attempt to decrease and/or homologues, analogues, derivatives, complexes, infections (see, e.g., Koerner et al., Biomaterials 23(14): esters, fragments, and Subunits thereof. 2835-40 (2002); Park et al., Biomaterials 19: 851-9 (1998); 0013 U.S. Pat. No. 6,428,579 to Valentini describes a and Lowy, N. Engl. J. Med. 339(8): 520-32 (1988)). coated implantable device having a gold layer on the Surface 0006 The adherence of eukaryotic cells and ECM pro to which bioactive molecules are attached through a gold teins to modified Surfaces has received much more attention sulfhydryl bond. than bacterial adherence (see Anselme et al., J. Biomed. Mater. Res. 49(2): 155-66 (2002); and Lowy, N. Engl. J. 0014 U.S. Pat. No. 6,503,556 to Harish et al. describes Med. 339(8): 520-32 (1988); and Hallab et al., Tissue Eng. methods of forming a coating on an implantable device or 7(1):55-71 (2001)). Different surface treatments have been endoluminal prosthesis. The coating in this reference can used to modify the topography and Surface chemistry of also be used for the delivery of an active ingredient, materials such as titanium (see, e.g., Puleo et al., Biomate radioopaque elements, or radioactive isotopes. rials 20: 2311-21 (1999); Lowey; and Hallab). The Lowey 0.015 U.S. Pat. No. 6,617,142 to Keogh et al. describes article describes one approach where the Surface is polished. methods for forming a coating of an immobilized biomol Another approach is to coat the Surface with an antimicro ecule on a Surface of a medical device to impart improved bial or protein resistant coating (see, e.g., Koerner, Nagaoka biocompatibility for contacting tissue and bodily fluids. US 2005/0220837 A1 Oct. 6, 2005 0016 U.S. Patent Publication No. 2003/0091609 A1 and 0030 FIG. 6 shows SEM images of hTERT fibroblast International Publication No. WO O2/O58752 both describe cells, after 48 h (left images) and 96 h (right images) of a medical device, as well as a method of making and using culturing on CAC and CPC surfaces. the same, containing a carrier (i.e., a polymer) and a poly 0031 FIG. 7 shows SEM images of hTERT fibroblast nucleotide or a cell that expresses an antimicrobial poly cells, after 48 h (left images) and 96 h (right images) of nucleotide. culturing on CC, CH, CHP, and CHR surfaces. 0.017. There is a need, however, for improved implants 0032 FIG. 8 shows SEM images of hTERT fibroblast that resist microbial growth. cells after 48 h (left image) and 96 h (right image) of SUMMARY OF THE INVENTION culturing on a CHC Surface. 0.018. The invention relates to implants coated with DETAILED DESCRIPTION OF THE hyaluronic acid or a derivative thereof.