Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-09-15
2004-04-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S426000
Reexamination Certificate
active
06723333
ABSTRACT:
The invention provides moulded items made from thermoplastic polyurethanes (TPUs), in particular medical articles such as central venous catheters which contain a homogeneous distribution of antibiotic substances, a process for the preparation thereof and preparation of the active substance-containing TPUs.
The use of polymer materials for diagnostic and therapeutic purposes has led to a significant technological advance in modem medicine. On the other hand the frequent use of these materials in medicine has led to a dramatic increase in so-called foreign body infections/polymer associated infections.
In addition to traumatic and thromboembolic complications, catheter-associated infections right up to sepsis represent serious problems when using central venous catheters in intensive medicine.
Numerous studies have shown that coagulase-negative Stapphylococci, the transient bacterium
Staphylococcus aureus
and various species of Candida are the main causes of catheter-associated infections. These microorganisms, which are always present on the skin, penetrate the physiological skin barrier when using the catheter and thus gain access to the subcutaneous region and ultimately the bloodstream. The adhesion of bacteria to the surface of the plastic material is thought to be the essential step for pathogenesis of foreign body infections. After adhesion of the skin bacteria to the polymer surface, the metabolically active proliferation of bacteria starts with colonisation of the polymer. This is accompanied by the production of a biofilm due to the bacterial excretion of extracellular glyclocalyx. The biofilm encourages adhesion of the pathogen and protects it from attack by specific cells in the immune system. In addition, the film forms a barrier which is impenetrable to many antibiotics. Following increased proliferation of the pathogenic bacteria on the surface of the polymer, septic bacteraemia may finally occur. Removal of the infected catheter is required in order to treat these types of infections since chemotherapy with antibiotics would require large, physiologically unacceptable, doses.
The frequency of bacterially induced infections involving central venous catheters is on average about 5%. Overall, central venous catheters are responsible for about 90% of all cases of sepsis in intensive medicine. The use of central venous catheters therefore not only involves a high risk of infection for patients but also causes very high secondary treatment costs (post-treatment, extended residence times in hospital).
These problems can only partly be solved by pre-, peri- or post-operative measures (e.g. hygiene precautions, etc.). A sensible strategy for preventing polymer-associated infections comprises modifying the polymer materials used. The objective of this modification must be the inhibition of bacterial adhesion and proliferation of bacteria which are already adhering, in order to avoid causal foreign body infections. This can be achieved by incorporating a suitable chemical substance in the polymer matrix (e.g. antibiotics), provided that the active substance incorporated can also diffuse out of the polymer matrix. In this case, release of the antibiotic can be extended over a relatively long period, which means that bacterial adhesion and proliferation on the polymer can be prevented for a correspondingly long period.
Methods for preparing antibacterial polymers for medical applications are already known. In the many processes described, addition of the active substance takes place 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 in the bulk phase of the polymeric carrier substance
d) Covalent bonding to the polymer surface.
DE-A-41 43 239, for example, describes a process for introducing active substances into the outer layer of medical articles (impregnation). In this case, the implantable device made of a polymer material is steeped in a suitable solvent. The polymer matrix then becomes modified so 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 embedded in the polymer matrix. After contact with the physiological medium, the active substance contained in 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 antimicrobially active coatings and methods of applying to the surfaces of medical devices are described. The coatings consist of a polymer matrix, in particular made of polyurethanes, silicones or biodegradable polymers, and an antimicrobial substance, preferably a synergistic combination of a silver salt and chlorhexidine or an antibiotic.
A common feature of all the processes mentioned is the fact that providing the medical working device with an antibiotic substance requires an additional working step, that is either pretreatment of the polymer material prior to processing or post-treatment of the moulded item when produced. This results in additional costs and involves extra time during production. Another problem associated with the processes is the use of organic solvents, most of which cannot be completely removed from the material.
The object of the invention was to provide moulded items with an antibiotic action, in particular medical articles such as catheters, which effectively prevent surface colonisation by bacteria for a relatively long period (2-4 weeks).
It has now been found that this can be achieved when moulded items are used which release a concentration of an antibiotic substance at the surface which can stop colonisation by bacteria for a relatively long period and which have a low surface roughness.
Thus, the object of the invention is moulded items made from thermoplastic polyurethanes which contain a homogeneous distribution of an antibiotic substance and which have a peak-to-valley surface roughness of <5 &mgr;m, preferably <2 &mgr;m, in particular <1 &mgr;m.
The antibiotic substances may in principal be any active substances which have a wide range of action against the pathogenic microorganisms involved in polymer-associated infections, in particular against coagulase-negative Staphylococci,
Staphylococcus aureus
and species of Candida. According to the invention, the antibiotic substances may also be used as active substance combinations in the moulded items, provided their effects are not antagonistic.
The active substances used must have sufficient (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 prevailing during incorporation; the active substance must therefore be sufficiently stable at the temperatures required for thermoplastic processing of the polymer material, 150 to 200° C., with residence times of 2 to 5 minutes.
Incorporation of the pharmaceutically active substance should not impair either the biocompatibility of the polymer surface or other desirable polymer-specific properties of the polymer material (elasticity, tear strength, etc.).
Suitable antibiotic substances are, for example, nalidixic acid and derivatives of nalidixic acid such as, for example, ciprofloxacin, norfloxacin, ofloxacin, pefloxacin, enoxacin, preferably ciprofloxacin, aminoglycosides such as, for example, gentamycin, kanamycin, amikacin, sisomycin, preferably gentamicin and kanamycin, macrocyclic antibiotics such as, for example, rifampicin or erythromycin, preferably rifampicin, bacitracin, mupirocin, thyrothricins such as, for example, gramicidin, tyrocidin, lincomycin, clindamycin or fusidic acid.
The active substances are preferably incorporated at a c
Albers Reinhard
Dujardin Ralf
Eberz Günther
Krasemann-Sharma Christina
Kreiss Wolfgang
Bayer Aktiengesellschaft
Bennett Rachel M.
Franks James R.
Gil Joseph C.
Page Thurman K.
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