Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2001-05-07
2003-08-12
Page, Thurman K. (Department: 1615)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S265000, C424S400000, C424S405000, C424S486000, C424S489000, C424S497000
Reexamination Certificate
active
06605069
ABSTRACT:
The invention relates to aromatic copolyesters comprising antimicrobially active substances in homogeneous distribution, processes for their preparation and their use in medical articles.
Vascular, catheter-associated infections are an important cause of morbidity and mortality in patients in intensive care. Recent studies demonstrate that in this group of patients up to 16% of those carrying catheters suffer from a catheter-induced sepsis. Approx. 2% of these patients show serious clinical complications, in particular septic shock or acute organ failure. An incidence of catheter infections which will increase further is to be expected in the future, since catheters are increasingly being used in modern intensive care treatment for invasive monitoring or treatment strategies, such as e.g. continuous haemofiltration.
Numerous studies have shown that coagulase-negative Staphylococci, the transient microbe Staphylococcus aureus and various Candida species are the main causative organisms of catheter-associated infections. These microorganisms, which are ubiquitous on the skin, penetrate through the physiological skin barrier when the catheter is applied and in this way enter into the subcutaneous region and fin ally into the bloodstream. Adhesion of the bacteria to the surface of the plastic is regarded as an essential step in the pathogenesis of foreign body infections. After adhesion of the skin microbes on to the polymer surface, proliferation of the bacteria follows, with colonization of the polymer. This is accompanied by a production of a biofilm by bacterial excretion of extracellular glycocalix. The biofilm assists adhesion of the pathogens and protects them from the body's own immune defence. The biofilm furthermore forms a barrier which is impenetrable to many antibiotics. After increased proliferation of the pathogenic microbes on the polymer surface, septic bacteriaemia may finally occur. Removal of the infected catheter is necessary for treatment of such infections, since chemotherapy with antibiotics would require non-physiologically high doses.
The use of central venous catheters therefore not only involves a high risk of infection for the patient, but also causes enormous secondary treatment costs.
These problems can be only partly solved by prophylactic measures, such as e.g. hygiene measures or routine endoluminal administration of antibiotics. A rational strategy for prevention of polymer-associated infections consists of modification of the polymeric materials used. The aim of this modification must be inhibition of the adhesion of bacteria and of proliferation of already-adhered bacteria, so that foreign body infections can be avoided causally in this way. This can be achieved e.g. by incorporating a suitable antimicrobially active substance into the polymer matrix (e.g. antibiotics), provided that the active compound incorporated can also diffuse out of the polymer matrix. In this case the release of the active compound can be extended over a relatively long period of time, so that the adhesion of bacteria and proliferation on the polymer is prevented for an appropriately longer period of time.
Methods for the preparation of antimicrobially equipped polymers for medical uses are already known. In the numerous processes described, the active compound is added by the following techniques:
a) Adsorption on to the polymer surface (passively or via surfactants)
b) Introduction into a polymer coating which is applied to the surface of a shaped article
c) Incorporation into the bulk phase of the polymeric carrier material
d) Covalent bonding to the polymer surface
DE-A-41 43 239 discloses, for example, a process for introducing active compounds into the outer layer of medical articles (impregnation). In this process, the implantable device of polymeric material is swollen in a suitable solvent. The polymer matrix is changed here such that a pharmaceutical active compound or an active compound combination can penetrate into the polymeric material of the implant. After removal of the solvent the active compound is enclosed in the polymer matrix. After contact with physiological medium the active compound contained in the implantable device is released again by diffusion. The release profile here can be adjusted by the choice of solvent and by varying the experimental conditions.
Polymer materials for medical uses which have coatings comprising active compounds are mentioned, for example, in EP-A 328 421. Processes for the preparation of the antimicrobially active coatings and methods for application to the surfaces of medical devices are described. The coatings comprise a polymer matrix, in particular of polyurethanes, silicones or biodegradable polymers, and an antimicrobially active substance, preferably a synergistic combination of a silver salt with chlorhexidine or an antibiotic.
All the processes mentioned have the common feature that equipping the medical working means with a pharmacologically active substance necessitates an additional working step, that is to say either pretreatment of the polymer material before processing or after-treatment of the shaped articles produced. This causes additional costs and involves an increased consumption of time on production. Another problem of the processes lies in the use of organic solvents, which usually cannot be removed without trace from the material.
The object of the invention was to provide new polymer materials which are suitable for the production of medical shaped articles for short-term implants, in particular catheters, and efficiently prevent colonization of the surface by microbes for a relatively long period of time (2-4 weeks).
Aromatic copolyesters which comprise antimicrobially active substances in homogeneous distribution and which release at the surface over a relatively long period of time a concentration of an antimicrobially active substance which suppresses colonization with germs have now been found. The invention therefore provides aromatic copolyesters which comprise an antimicrobially active substance in homogeneous distribution.
Possible antimicrobially active substances are in principle all active compounds which have a broad action spectrum against the pathogenic microorganisms involved in polymer-associated infections, in particular against coagulase-negative Staphylococci, Staphylococcus aureus and Candida species. The antimicrobially active substances can also be used according to the invention as active compound combinations in the shaped articles, as long as they are not antagonistic in their actions.
The active compound used must have an adequate (chemical) stability in the polymer matrix. Furthermore, the microbiological activity of the active compound must not be impaired in the polymer matrix and under the process conditions of incorporation, and the active compound must thus be stable at the temperatures of 150 to 200° C. required for thermoplastic processing of the polymeric material.
The incorporation of the pharmaceutically active substance should impair neither the biocompatibility of the polymer surface nor other desirable polymer-specific properties of the polymeric material (elasticity, tear strength etc.).
Suitable substances having an antibiotic action are, for example:
earlier quinolones, such as e.g. nalidixic acid, pipemidic acid and cinoxacin,
more recent quinolones, such as e.g. ciprofloxacin, norfloxacin, ofloxacin, pefloxacin and enoxacin, preferably ciprofloxacin,
aminoglycosides, such as e.g. gentamycin, kanamycin, amikacin, sisomycin, tobramycin and netilmicin, preferably gentamycin and kanamycin,
macrolides, such as e.g. erythromycin, clarithromycin and azithromycin,
polypeptides, such as e.g. bacitracin, mupirocin and thyrothricin (combination of gramicidin and tyrocidin,
lincomycins, such as e.g. lincomycin and clindamycin
antimycobacterial agents, such as e.g. rifampicin or
fusidic acid.
The antimicrobially active substance can also be an antiseptic or a disinfectant, as long as the substance used has an adequate activity against the infection-causi
Albers Reinhard
Dujardin Ralf
Fröde Rita
Hobler Hartwin
Pudleiner Heinz
Bayer Aktiengesellschaft
Franks James R.
Gil Joseph C.
Page Thurman K.
Preis Aron
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