Electrolysis: processes – compositions used therein – and methods – Electrolytic synthesis – Preparing nonmetal element
Reexamination Certificate
2000-10-19
2002-11-19
Phasge, Arun S. (Department: 1741)
Electrolysis: processes, compositions used therein, and methods
Electrolytic synthesis
Preparing nonmetal element
C205S701000, C204S242000, C204S260000, C204S272000
Reexamination Certificate
active
06482309
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and devices for transferring anti-infective activity to medical devices through electrolytic generation of elemental iodine, allowing for its transfer to the polymer base of urinary and venous catheters, wound drain tubes, and other medical devices, conferring to such devices prophylactic and therapeutic treatment of implant-linked infections.
BACKGROUND OF THE INVENTION
Introduction of medical devices implanted into the body can lead to serious nosocomial infections. Implanted medical devices (e.g., venous and arterial catheters, neurological prostheses, wound drains, urinary “Foley” catheters, peritoneal catheters, and other lumenal indwelling devices), while sterilized and carefully packaged to guard against introduction of pathogens during implantation, pose a risk during insertion, and subsequently. During insertion bacteria can be picked up from the skin and carried into the insertion site where bacterial colonization may ensue. In the case of urinary and venous catheters, especially those used long term, there is a significant threat of microbial growth along the exterior surface of the catheter. This can lead to chronic urinary tract infections (CUTI), or septicemia in the case of venous and arterial catheters, thrombolytic emboli caused with infections introduced by the catheter, and other life-threatening complications, especially among the elderly. In cerebrospinal fluid shunt catheters the incidence of infections is unacceptably high, especially in neonates, varying from 2 to 31% depending upon the age group and hospital setting in which the surgery is conducted.
Methods aimed at circumventing this problem have included irrigating the implant site with antibiotic, applying various antibiotic ointments or antibiotic impregnated sponges near the exterior opening by which infection most likely occurs, impregnating the polymer base coating the implant device with antibiotics, or silver, either as a heavy metal or in combination with antibiotics, or treatment of patients systemically with antibiotics. Despite the foregoing attempts at preventing infections, these methods of preventing and treating infections have not proven satisfactory. There remains a need in the art to mitigate the risk of infection from such devices.
It is known, for example, that the long term uses, and misuse, of antibiotics often results in the selection of antibiotic resistant strains. Hence, in general, systemic antibiotic therapy is ill advised and ineffective in warding off CUTI, for example. The secondary side effects of systemic antibiotic treatments can also pose a serious risk to many patients. Furthermore, in many implant sites, the formation of fibrous tissue around the implant site reduces the supply of blood to the implant cavity thereby precluding systemic antibiotic treatment of the critical space between the implant and capsular endothelial wall. In the case of a urinary catheter (e.g., Foley catheter), antibiotics injected as a coating in the urinary canal may be washed out during drainage through leakage of some urine along the urinary tract outside the catheter, or resorbed before they can achieve sufficient levels to effectively kill bacteria growing within localized regions of the urinary tract.
It can thus be appreciated that there is a pressing need for the development of better methods of preventing and treating infections caused with the implantation of medical devices into body cavities, particularly for the development of methods and devices which circumvent the problem of selecting out antibiotic resistant organisms. The problem is particularly acute since it is known that when catheters, and other indwelling lumenal devices, are inserted into body cavities such as the urinary tract, venous or arterial vessels, or into wound or surgical sites, a biofilm forms rapidly on the walls of the implant device. Bacteria then propagate free from attack by the body's own phagocytic defense system, and also free from systemic antibiotic treatments (Gristina, A.G., Science 237: 1588-1595 (1987); Zhang, X. et al., Medical Plastics and Biomaterials, Nov. 1997, pp. 16-24).
Free elemental iodine is attractive as an anti-infective agent. There are no known organisms which have developed resistance against its oxidizing activity in attacking critical sulfhydryl groups, and other functional groups in proteins, essential for bacterial survival (Second Asian Pacific Congress on Antisepsis in Postgrad. Med. J. 69 (suppl. 3), 1993: S1-S134; Third Asian Pacific Congress on Antisepsis in Dermatology 195 (suppl. 2), 1997: S1-S120). A few parts per million (ppm) in solution is sufficient to kill bacteria and viruses (LeVeen et al. (1993) Gynecology & Obstetrics 176: 183-190; Barabas, E. S. and Brittain, H. G. (1998) in Analytical Profiles of Drug Substances and Excipients (ed., Brittain, H. G.) Vol. 25, AP, San Diego, pp. 341-462). On the other hand, because of its high degree of diffusion through water, air and lipids, and its reactivity as an oxidizing agent, elemental iodine is difficult to handle in a clinical setting.
Methods of stabilizing iodine in solution illustrated by the formulation, Povidone-iodine, for example, are well known to those in the art. This formulation has been tried without satisfactory success in conferring to catheters anti-infective properties. Povidone-iodine washes free of devices as a coating of insufficient duration to significantly reduce the incidence of infections brought on following implantation, particularly in complex biological media. Jansen et al. (J. Antimicrobial Chemotherapy 30: 135-139 (1992)), and Kristinsson et al. (J. Biomaterials Applications 5: 173-184 (1991)), sought to confer to catheters anti-infective activity by preloading the lumen with iodine complexed with polyvinylpyrrolidone (PVP). While they were able to demonstrate weak anti-infective activity in aqueous buffered solutions, this strategy proved unsatisfactory in complex media. Jansen reported that the activity conferred by this technique lasted for less than 3 hours in serum.
Povidone-iodine as it is commercially formulated with a total iodine content of 10,000 ppm also introduces a high iodine exposure level to the patient of which only about 1 ppm is free iodine, the form necessary to affect microbial killing. PVP, the binding agent used in trapping iodine in aqueous solutions in a bound form, is also problematic in retarding wound-healing (LeVeen et al. (1993) Gynecology & Obstetrics 176: 183-190). The short-lived retention of Povidione-iodine coatings on implant devices, the fact that binding agents such as PVP aggravate wound-healing, and the fact that the free form of iodine in Povidone-iodine at 1 ppm is below the essential ~2 ppm level of free iodine required for efficient microbial killing, points out the need for a better method of presenting iodine as an anti-infective agent to catheters, and other indwelling implant devices (e.g., wound drains).
Morain and Vistnes (Plastic & Reconstructive Surgery 59: 216-222 (1977)) sought to impregnate silicone discs with elemental iodine by soaking discs in 95% ethanolic solutions in which crystalline iodine had been dissolved, and then tested the discs for anti-infective activity. While they were able to demonstrate the release of anti-infective activity in their iodine impregnated disc samples, they concluded that the use of iodine was “contraindicated” because of concern that it would add to the vinyl group of polymethylvinylsiloxane in the formulations they used, potentially altering “the substance sufficiently that an entirely new set of physiochemical properties might result.” It is also apparent that the method of impregnating an implant using crystalline iodine and an alcoholic solution is impractical in a clinical setting. Iodine crystals in combination with alcohol can cause severe chemical burns if put into direct contact with tissues, it is difficult to control dosing of crystalline iodine in a reliable fashion, and messy working with mixtures of cryst
Fellman Jack H.
Green Terrence R.
Heller Ehrman White & McAuliffe LLP
OxiBio, Inc.
Phasge Arun S,.
LandOfFree
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