The invention relates to a device for administering drugs and for influencing the effects of drugs.
In connection with the administration of drugs, the principal problem is that they are generally applied without or with only insufficient localising measures. Therefore, not only an affected body region will come in contact with the active substances, but in fact, healthy body cells will also be affected and possibly permanently damaged by the administered substances.
Another problem affecting the effectivity of drugs is associated with the fact that the cell membranes to be penetrated and the biochemical protective covers of cells constitute an obstacle to the drugs. For example, bacteria may become resistant to antibiotics in this way, and cancer cells may survive despite of the application of cytostatics. It may also be problematic to apply growth-enhancing substances or other cellular active substances so that the cell membranes are penetrated.
But even if the active substance has reached the interior of the cell, there may be intracellular reaction impediments which are, in many cases, simply associated with the kinetics of the required chemical reaction, i.e. particularly with the absence of the activation energy required for the reaction.
The object of the invention is to address the named problems individually or collectively, in particular, to concentrate drugs locally, to enhance the penetration of cell membranes, and to influence the kinetics of the intracellular reaction.
Said object is solved by the features of the independent claim.
Advantageous embodiments of the invention are described in the dependent claims.
The invention relates to a device comprising a voltage source, an electric conductor connected to an electric pole of the voltage source and acting as an electrode, and a substrate arranged in the electromagnetic field which forms in the vicinity of the electric conductor when the voltage source is active, wherein the substrate serves to accommodate drugs. Such a device can be placed in the direct vicinity of the affected body region. With the voltage source or the electromagnetic field formed in the vicinity of the electric conductor the release of the drugs accommodated by the substrate can be accomplished or enhanced. More specifically, the term “substrate” used here can, also be replaced by the term “matrix”. Body regions located away from the device placed in a localised manner will not be or will only scantly be reached by the locally applied drugs. Further, the presence of an electric field gradient will have the effect that the penetration of the drugs through the cell membranes is facilitated. The electric field may also cause a concentration of ionic messenger substances (e.g., Ca2+), so that the penetration through the membrane pore opening is thereby also enhanced.
It is particularly preferred that a device for influencing an electric voltage generated by the voltage source is provided. In this way the release of drugs from the substrate can be controlled. The device may then, for example, be designed so that an increased drug release will take place when the electric voltage is increased.
Preferably, the electric conductor connected to the electric pole is a metal wire. In principle, any electric conductor can be used. A metal wire, particularly a stainless steel wire, however, constitutes a useful possibility to transfer the electric potentials generated by the voltage source.
Usefully, it is contemplated that the metal wire carries the substrate. Aside from the electric properties of the metal wire required for the invention, this also provides a safe and flexible possibility to accommodate the substrate containing the drugs. The substrate formed of an insoluble matrix such as PMMA (polymethyl methacrylate) and having the form of, for example, spheres or ellipsoids may be accommodated by a carrier, usually a steel wire, similar to a pearl necklace, which is implanted in the area of an infection, for example, a bone infection.
In connection with the present invention, it is particularly useful that the voltage source comprises a transducer which generates an electric voltage in the presence of an external magnetic field. An external alternating magnetic field can generate an electric voltage in a transducer which is, in particular, realised by a coil. Thus, the variation of the external magnetic field can also induce a variation of the electric voltage and thus of the release rate of the drug. Further, the reaction kinetics can be influenced by the alternating magnetic field in such a way that the reaction of the cell substances with the drugs can already take place at a low activation energy.
It may also be contemplated that the voltage source comprises a battery. Such a battery may, in particular, be provided in addition to a transducer which generates an alternating electric field, namely for superimposing the alternating voltage with a direct voltage component.
The present invention is further developed in a particularly useful way in that an at least partly electrically conductive implant is electrically coupled to a pole of the voltage source. The invention can be deployed in an advantageous manner particularly in the area of endoprostheses and osteosynthesis means. On the one hand, it is known that the presence of low-frequency alternating magnetic fields and the electric stimulation of implants caused thereby by means of a transducer have a positive influence on the encouragement and the differentiation of the tissue growth. Exemplary systems are described in the following documents: DE 199 28 449 C1, DE 10 2004 024 473 A1, DE 10 2006 018 191 B4, DE 10 2007 049 542 A1, and DE 10 2007 063 027 A1. In the devices and methods shown therein, low-frequency alternating electric potentials are generated in implants by exposing an affected body part to an alternating magnetic field. For a long time, it has been shown in numerous clinical applications of this technology to chronically therapy-resistant, in most cases infected bone defects, cysts, and tumour metastases as well in clinical experimental studies that an optimum healing effect is achieved by using implants as sources of extremely low-frequency sinusoidal alternating electric potentials in the bone region abutting on the support metal. The same applies to endoprostheses. The technology for transmission functions according to the transformer principle: the injured or affected body region is flooded with an extremely low-frequency sinusoidal magnetic field having a frequency of approximately 1 to 100 Hz—preferably of 4 to 20 Hz—and a magnetic flux density of 0.5 to 5 mT (5 to 50 Gauss) generated by a waveform generator in one or more—primary—external current coils into which the body part provided with the implants is introduced. These extremely low-frequency electromagnetic fields permeate the tissue including any present clothing and/or a cast, as well as the non-magnetic (austenitic) support metals of the implants largely without loss. A—secondary—coil arrangement, the so-called transducer, is implanted in electric contact with these. In this way, the electrical potentials induced in the transducer are rendered effective in the area of the bone lesion as well as generally in the tissues adjacent to the implants. With the aid of the invention, it is now realised that on the one hand, the implants are electrified in the described manner. On the other hand, a local administration of drugs using the same means is enabled.
According to a specific embodiment of the invention, it is contemplated that a tooth-jaw bridge is provided which at least partly forms or carries the substrate and which further contains the voltage source as well as the electrodes interacting with the voltage source. Such a tooth-jaw bridge may, owing to its bone-generating effect, replace the complicated mechanical callus distraction of the alveolar jaw area. Further, infected tooth prostheses in the form of the enossal jaw implants—commonly referred to as peri-implantitis—can be treated successfully. The electrodes of the tooth-jaw bridge are, in this case, preferably arranged on the buccal and lingual sides. Direct or alternating voltages in the range from 500 to 700 mV are achievable between the electrodes by means of which the bone growth is stimulated and a strongly antibiotic effect is developed. Bacteria biofilms are detached from their carrier, for example, a dental prosthesis formed of a titanium alloy, and its virulence due to which approximately 20 to 30 percent of all dental prostheses are still presently lost is brought to an end. Aside from the treatment of the peri-implantitis, this can also be prevented by the specific embodiment of the invention comprising the tooth-jaw bridge. At the tooth gap in the jaw, bone growth is stimulated by the tooth-jaw bridge and the electro-osteotherapy thereby enabled so that the jaw is prepared for a later implantation. At the same time, an infection prior to implantation is excluded by the antibacterial effect of the tooth-jaw bridge.
In this connection, it is particularly useful that the tooth-jaw bridge contains two bridge abutments and a bridge platform, that the voltage source is located in the bridge platform, and that an electrode connected to a respective pole of the voltage source as well as the substrate directly contacting gingiva and mucosa are arranged in the bridge abutments, respectively.
According to a preferred embodiment of the device for jaw treatment, it is contemplated that at least one component carrying the substrate and the electrode interacting with the voltage source is manufactured with the aid of a plastic impression of a body part to be contacted. Due to the strongly rippled and profiled surfaces of the tooth and jaw region, establishing a sufficient contact between the electrodes and the body parts to be contacted using conventional tools is problematic. For example, a support plate as used in the osteosynthesis of fractures of long hollow bones would lose stimulating effectiveness due to the lack of electric contact. Also in regard to the release of drugs, a simple plate would not be ideal, as the release depends on the size of the surface of the substrate relative to the dimensions of the defect area. These problems are solved by the use of a plastic impression. Preferably, buccal as well as lingual plastic impressions are prepared onto which then an electrically conductive, porous and compressible layer is finally applied. This layer forms the substrate for the drugs. It is possible to apply a conducting surface layer which particularly serves to contact the connections brought up from the voltage source onto the impressions prior to the application of the electrically conductive, porous, and compressible layer. The plastic impressions are preferably held by a bracket which might also serve as a carrier for the pick-up coil and/or the battery and/or a direct current/alternating current generator. The electrically conductive, porous, and compressible layers may wholly or partly consist of an electrically conductive plastic material, for example, polymers which can be converted into an electrically conductive form by doping and/or coating.
It may also be contemplated that at least one component forming the substrate and the electrode interacting with the voltage source is formed of an at least partly conductive and absorptive material. The fabrication of plastic impressions requires a certain effort. This can be avoided by manufacturing the entirety of the electrodes from a sponge-like elastic material having a good electric conductivity. The same materials come into consideration as the ones used for the electrically conductive, porous and compressible coating of the plastic impressions. While in case of the plastic impressions, the electrically conductive structures are preferably applied exclusively where an electric contact to the body is to be established and also where the drugs are to be released, it is reasonable in case of the electrodes consisting entirely of a porous material to electrically insulate the buccal and lingual areas and also to prevent the release of drugs in these places by converting the surfaces into a liquid-impermeable form there, for example, by coating.
According to a preferred embodiment of the invention, it is contemplated that the substrate at least partly consists of polymethyl methacrylate. Polymethyl methacrylate (PMMA) is a biologically safe active substance which is, furthermore, suitable to accommodate drugs and to release them at the location of the illness.
It is particularly preferred that the substrate at least partly consists of a magnesium-calcium alloy or a magnesium-zinc-calcium alloy. One drawback of the use of PMMA becomes obvious when it is explanted from the tissue in which the substrate chain has become more or less ingrown so that a larger surgical operation is required to remove it. This drawback can, according to the invention, be avoided by the use of substrates consisting of a biocompatible material which is soluble in the tissue. A particularly suitable substrate for this purpose is magnesium in alloys containing calcium and/or zinc and/or also lithium and/or rare earths. Due to its direct affinity with calcium phosphate, the main component of the hard bone substance, the alloy of magnesium and calcium is particularly suitable for the antibiotic treatment of infected bone areas. A magnesium alloy may also serve as a carrier for bone growth factors, for example BMP (bone morphogenetic protein) or TGF Beta (transforming growth factor beta). A further advantage of magnesium as a drug carrier in the arrangement according to the invention is, its electric conductivity which at 22.6 S/m, ranges between aluminium (36.6 S/m) and brass (15.5 S/m).
The invention further consists of a system comprising a device according to the invention to be attached to or to be introduced into a human body and a device for generating a magnetic field outside of the body.
Further, the invention relates to a method for producing a device according to the invention, wherein, in the course of the production of the device, at least one component carrying the substrate and the electrode interacting with the voltage source is produced by means of a plastic impression of a body part to be contacted.
The invention was primarily described in connection with implants above. However, it is not limited to this. Another useful application is, for example, a wound dressing comprising an electrode network and an antibiotic, particularly gentamyzin, wherein a collagen mesh forms the substrate.
The invention is based on the finding that with consistent technology, the principles of the electro-osteotherapy can be applied and, at the same time, that the issues in connection with the administration of drugs described in the introduction can be addressed. Drugs can be administrated locally, the penetration of cell membranes is facilitated, and the kinetics of the intracellular reaction is accelerated. The presence of magnetic fields can also be used in another way, namely in which the active ingredients are coupled to a paramagnetic carrier. In this case, the carrier contains nanoparticles having the required magnetic properties. By placing the area of the patient where the active substances are to be concentrated in a spatially variable magnetic field, i.e., what is commonly referred to as a gradient magnetic field, so that the substances are concentrated in the area of the cells to be treated, for example, in the area of a tumour, other body regions may remain unaffected by the active substances to be administered. The active substances are thus applied locally in the vicinity of the body region to be treated, and they are then concentrated in the affected tissue due to the magnetic gradient fields. This method is also referred as “magnetofection”.
The invention will now be explained by way of example with the aid of particularly preferred embodiments with reference to the accompanying drawings in which:
In the following description of the drawings identical numerals designate the same or comparable components.
If the device 10 according to
Exemplary operating modes may be characterised as follows:
The features of the invention disclosed in the above description, in the drawings as well as in the claims may be important for the realisation of the invention individually as well as in any combination.
10 device
12 voltage source
14 voltage source
16 voltage source
18 electrodes
20 electrodes
22 substrate
24 metal wires
26 transducer
28 battery
30 battery
32 implant
34 implant
36 screw
38 screw
40 tooth-jaw bridge
42 bridge abutment
44 bridge abutment
46 bridge platform
48 substrate
50 spacer
52 accommodation device
54 accommodation device
56 capacitor
58 bone
60 marrow nail
62 locking screw
64 locking screw
66 screws
68 bone
70 electric line
72 cavity
74 opening
76 tooth spacer
80 transducer
82 component
84 jaw
86 tooth
88 tooth
90 component
92 component
94 layer
96 layer
98 bracket
100 insulated area
102 insulated area
Number | Date | Country | Kind |
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10 2009 049 175.9 | Oct 2009 | DE | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/EP2010/006271 | 10/13/2010 | WO | 00 | 6/4/2012 |