Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Biocides; animal or insect repellents or attractants
Reexamination Certificate
2001-05-07
2002-09-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Biocides; animal or insect repellents or attractants
C424S409000, C424S484000, C424S486000
Reexamination Certificate
active
06455059
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to polyether block amides (PEBAs) which contain homogeneously distributed antimicrobial active substances, a process for their preparation and their use in medical articles.
BACKGROUND OF THE INVENTION
Vascular, catheter-associated infections are an important reason for the morbidity and mortality of patients in intensive care units. Recent studies have shown that up to 16% of patients fitted with a catheter in this group of patients suffer catheter-induced sepsis. About 2% of these patients exhibit severe clinical complications, in particular endotoxic shock or acute organ failure. In the future, a further increase in the incidence of catheter infections may be expected since catheters are increasingly being used in modem intensive therapy during invasive monitoring or treatment strategies such as, for example, continuous haemofiltration.
Many studies have shown that coagulase-negative Staphylococci, the transient bacterium Staphylococcus aureus and various species of Candida are the main sources of catheter-associated infections. These microorganisms, which are always present on the skin, penetrate the physiological skin barrier during application of the catheter and thus gain access to the subcutaneous region and ultimately the bloodstream. The adhesion of bacteria to the surface of plastics is regarded as an essential step during the pathogenesis of foreign body infections. After adhesion of skin bacteria to the polymer surface, there follows proliferation of the bacteria and colonisation of the polymer. This is accompanied by the production of a biofilm due to bacterial excretion of extracellular glycocalyx. The biofilm supports adhesion of the pathogen and protects it from the body's own immune defence system. In addition, the biofilm forms a barrier which cannot be penetrated by many antibiotics. After increased proliferation of the pathogenic bacteria on the polymer surface, septic bacteraemia may finally occur.
Removal of the infected catheter is required to treat these types of infections since chemical treatment with antibiotics would require physiologically unacceptable large doses.
The use of central venous catheters therefore involves not only a high risk of infection for patients, but also results in enormous therapeutic follow-up costs.
This problem can only be solved to a partial extent by prophylactic measures such as, for example, hygienic precautions or routine endoluminal application of antibiotics. A rational strategy for preventing polymer-associated infections comprises modifying the polymer material used. The objective of this modification must be the inhibition of bacterial adhesion and the proliferation of bacteria which have already adhered, in order to prevent causal foreign body infections. This can be achieved, for example, by incorporating a suitable antimicrobial active substance in the polymer matrix (e.g. antibiotics) assuming that the active substance incorporated can also diffuse out of the polymer matrix. In this case, release of the active substance can be extended over a long time so that bacterial adhesion and proliferation on the polymer is prevented for a correspondingly long time.
Methods for the preparation. of polymers provided with antimicrobial systems for medical use are already known. In the many processes which have been described, the active substance is added using the following techniques:
a) adsorption on the polymer surface (passively or via surfactants)
b) introduction in a polymer coating which is applied to the surface of a moulded item
c) incorporation within the bulk phase of the polymeric supporting material
d) covalent bonding to the polymer surface.
DE-A-41 43 239, for example, describes a process for introducing (impregnating) active substances into the outer layer of medical articles. Here, the implantable device made of a polymer material is steeped in a suitable solvent. The polymer matrix is then modified in such a way that a pharmaceutically active substance or combination of active substances can penetrate into the polymer material of the implant. After removing the solvent the active substance is included within the polymer matrix. Following contact with a physiological medium, the active substance contained within the implantable device is released again by diffusion. The release profile can be adjusted by the choice of solvent and by varying the experimental conditions.
Polymer materials for medical applications which have active substance-containing coatings are mentioned, for example, in EP-A 328 421. Processes for preparing the antimicrobial active coatings and methods for applying these to the surfaces of medical devices are described. The coatings consist of a polymer matrix, in particular polyurethanes, silicones or biodegradable polymers, and an antimicrobial active substance, preferably a synergistic combination of a silver salt and chlorhexidine or an antibiotic.
A common feature of all the processes mentioned is that providing the medical device with an antimicrobial active substance requires an additional working stage, that is either pre-treatment of the polymer material prior to processing or post-treatment of the moulded item produced. This causes additional costs and results in an increase in the production time. Another problem resulting from the processes is the use of organic solvents, which generally cannot be removed from the material without leaving some traces in the material.
SUMMARY OF THE INVENTION
The object of the invention was to provide new polymer materials which are suitable for the production of medical moulded items for short-term implants, in particular catheters, and effectively prevent surface colonisation by bacteria for a long period (2-4 weeks).
Polyether block amides which contain homogeneously distributed antimicrobial active substances, which release a concentration of antimicrobial active substance at the surface sufficient to suppress colonisation by bacteria for a long time, have now been found. Thus the invention provides polyether block amides which contain a homogeneously distributed antimicrobial active substance.
DETAILED DESCRIPTION OF THE INVENTION
In principal, all active substances which have a broad activity spectrum towards the pathogenic microorganisms involved in polymer-associated infections, in particular towards coagulase-negative Staphylococci,
Staphylococcus aureus
and the Candida species, may be considered suitable as antimicrobial active substances. According to the invention, the antimicrobial active substances may also be used as active substance combinations in the moulded items, provided their effects are not antagonistic.
The antimicrobial active substance used must exhibit adequate (chemical) stability in the polymer matrix. In addition, the microbiological activity of the active substance should not be impaired in the polymer matrix and under the process conditions for incorporation. The active substance must therefore be stable at the temperatures of 150 to 200° C. required for thermoplastic processing of the polymer material.
Incorporation of the pharmaceutically active substance should not impair either the biocompatibility of the polymer surface or other polymer-specific properties of the polymer material (elasticity, resistance to tearing, etc.).
Suitable antibiotic active substances are, for example:
older quinolones such as e.g. nalidixic acid, pipemidic acid and cinoxacin,
newer quinolones such as e.g. ciprofloxacin, norfloxacin, ofloxacin, pefloxacin, enoxacin, preferably ciprofloxacin,
anminoglycosides such as e.g gentamicin, kanamycin, amikacin, sisomycin, tobramycin, netilmicin, preferably gentamicin and kanamycin,
macrolides such as e.g erythromycin, clarithromycin and azithromycin,
polypeptides such as e.g bacitracin, mupirocin, thyrothricin (a combination of gramicidin and tryrocidin),
lincomycins such as e.g. lincomycin and clindamycin,
antimycobacterial agents such as e.g. rifampicin or
fusidic acid.
The antimicrobial active substance may also be an antiseptic or a
Albers Reinhard
Dujardin Ralf
Hobler Hartwin
Pudleiner Heinz
Simon Joachim
Bayer Aktiengesellschaft
Franks James R.
Fubara Blessing
Gil Joseph C.
Page Thurman K.
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