DE102006041495A1 - Substance mixture, useful for locally limited of magnetic nanoparticle within or directly at the edge of tumor affected physical tissue, where the magnetic particle is mixed with a fluid thixotropic carrier substance - Google Patents

Abstract

Substance mixture for local deposition of magnetic particle (which is mixed with a fluid thixotropic carrier substance) in a medium, preferably for locally limited deposition of magnetic nanoparticles within or directly at the edge of tumor affected physical tissue, is claimed, where the magnetic nanoparticle in the substance mixture is provided for controlled magnetic field heating in tumor treatment. An independent claim is included for an application kit for use of the substance mixture, comprising: at least an ampule (ampule A), which contains magnetic nanoparticle suspended in an aqueous solution; at least an other ampule (ampule B) with the fluid thixotropic carrier substance; one or more sterilely packed syringes with cannula for mixing the content of the ampule (A) and (B); one or more probes with cannula for injecting the mixture of the ampule content into the medium; optionally one or more thermosensor for application; and an instruction for administration and optionally dosage. ACTIVITY : Cytostatic. MECHANISM OF ACTION : None given.

Description

The The invention relates to a mixture of substances, preferably magnetic Nanoparticles with stable high and reproducible concentration as well as marked demarcation locally in a medium, in particular in tumor-containing organic Tissue to be incorporated. The invention is applicable wherever magnetic particles for good and practicable enrichment in an object, such as body, materials, Substances etc., defined to be locally enriched. Further is an application kit for administration of the substance mixture proposed.

For medical Applications to which the use of such a substance mixture not limited is supposed to be the deposition of magnetic nanoparticles in the body of a be highlighted living organism. With the liquid substance mixture The magnetic particles are injected into the body and there with local delimitation to healthy tissue in organic changed Tissue zones deposited to make this more malignant for thermal treatment To heat diseases by a magnetic field.

For this Not only does the substance mixture need to be injectable well and practicably but after the injection this should be with high particle concentration, Homogeneous particle distribution and with striking demarcation to accumulate healthy tissue locally in the designated tissue zones to not risks of unwanted Side effects of warming enter this introduced by the substance mixture magnetic nanoparticles to have to. Such risks not only concern the unnecessary harm to neighboring healthy ones Body tissue but also the dangerous one wrong or inadequate treatment of diseased tissue, if the particles for thermal treatment of the same is not local in the desired Density and homogeneity enrich as intended, but spread uncontrollably in the body.

The effect intended for tumor treatment based on the dissipation of magnetic field energy into heat, which occurs as soon as the magnetic nanoparticles introduced into the body tissue for deposition are exposed to a high frequency external magnetic field, is highly dependent on the characteristics of this high frequency magnetic field as well as on the introduced ones Magnetic particles and their distribution in the tissue (eg R. Hergt, R. Hiergeist, I. Hilger, WA Emperor: Magnetic nanoparticles for thermoablation, Recent Res. Devel. Mat. Sci., 3, 2002, 723 ).

The application of the magnetic particles in the tumor to be treated is carried out in a known manner by injection of an aqueous suspension (eg. I. Hilger, W. Andrä, R. Bähring, A. Daum, C. Grosser, R. Hergt, WA Kaiser: Evaluation of temperature increase with different amounts of magnetite in liver tissue samples. Investigative Radiology 32, 1997, 705-712 ; I. Hilger, W. Andrä, R. Hergt, R. Hiergeist, H. Schubert, WA Kaiser: Electromagnetic heating of breast tumors in interventional radiology: in vitro and in vivo studies in human cadavers and mice. Radiology 218/2, 2001, 570-575 ).

One great The problem is the inhomogeneous and hardly controllable distribution of Magnetic particles in the tumor tissue, which has the consequence that both individual Tissue parts overheated as well as others insufficient heated which allows tumor cells to survive can. About that In addition, the specific heat output currently available Magnetic particles are relatively low, so not only a high magnetic Field energy, but also high particle concentrations in the tumor for its effective control by overtemperature (Hyperthermia or thermoablation) may be required.

As practice shows, to date, a sufficiently uniform particle distribution especially in biological tissue problematic because of its inhomogeneity and texture causes that the injected suspension liquid flows along internal interfaces in the Tissue spreads. Tumor tissue is superior to healthy tissue specified firmer consistency and inhomogeneity, so that the fluid injected into the tumor it has the tendency to 'flow out' of the tumor area and the adjacent healthy tissue to infiltrate. This changed However, the particle concentration and homogeneity in the tumor tissue, causing problems in the subsequent treatment of the patient leads. additionally would be at the treatment, as described, the adjacent healthy tissue affected to the detriment of the patient.

Also in the US 6,514,481 describes an injection of magnetic nanoparticles in an aqueous-liquid suspension into tissues of a living organism. Neither stable nor loose tissue, however, a way is disclosed to solve the problems identified uncontrolled spread in the tissue.

In order to be able to control the particle distribution at least within certain limits, as slow as possible an infusion of the aqueous suspension is recommended in the literature (for example. Jordan, A., Scholz, R., Wust, P., Fahling, H., Krause, J., Wlodarczyk, W., Sander, B., Vogl, T., Felix, R .: Int. J. Hyperthermia, 13, 1997, 587 ). However, the result at reasonable infusion times is still unsatisfactory, to this a reproducible To justify treatment with predictable chances of success. In addition, a relatively high concentration (above 10 mg of magnetic material per cm ^{3 of} tumor tissue) would have to be set by the injection in order to achieve a sufficient heat effect for the tumor treatment. With the previous injection fluids, it is currently not possible for the abovementioned reasons, in particular, to achieve this high particle concentration in the tumor-affected tissue with a homogeneous particle distribution. Lower particle concentrations would in turn require immensely complex and costly high-energy magnetic fields.

It is also known (eg E. Faglia: Antidiabetic therapy in diabetic patients with coronary heart disease Minerva Med. 2003, 94, 387-399 ; S. Matthaei, A. Hamann: Current insulin therapy, Treatment with new short-acting and retard insulin analogs, Fortschr Med. 1997, 115, 35-36 ; V. Martina, M. Tagliabue, M. Maccario, G. D'Antona, F. Camanni: Comparison of Monotard and Ultratard insulin at bedtime in a model of optimized insulin therapy in Italy, Diabete Metab. 1989, 15, 372-374 ; HW Bellwinkel: Experiences with a new retard insulin, Dtsch Med Wochenschr. 1954, 79, 1896-1899 ) to inject into the tissue aqueous-liquid preparations containing chemical substances (not corpuscles), which are released delayed or locally effective. This delay is due to the pharmacological (galenic) preparation (for example, sparingly soluble salt). The injections are usually done in less perfused tissue such. B. fatty tissue. By way of example, the sustained-release insulin depot injection may be mentioned here. However, this method is not intended and also not suitable for accumulating magnetic particles locally locally in tissue. Incidentally, the injection of this aqueous-liquid preparation would lead to the undesired side-effects and risks already described above.

Of considerable disadvantage is also the stimulating effect of insulin on the proliferation of some tumor cells (eg. A. Mawson, A. Lai, JS Carroll, CM Sergio, CJ Mitchell, B. Sarcevic: Estrogen and insulin / IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-myc and cyclin D1 , Mol Cell Endocrinol. 2005, 229, 1-2, 161-173 ).

Furthermore, the injection of viscous fluids (gels) into the tissue is known (eg. S. von Buelow, D. Heimburg, N. Pallua: Efficacy and safety of polyacrylamide hydrogel for facial soft-tissue augmentation, Plast Reconstr Surg. 2005, 116, 1137-1146 ; W. de Cassia Novaes, A. Berg: Experiences with a new nonbiodegradable hydrogel (Aquamid): a pilot study, Aesthetic Plast Surg. 2003, 27, 376-380, C. Bergeret-Galley, X. Latouche, YG Illouz: The Value of a New Filler Material in Corrective and Cosmetic Surgery: DermaLive and DermaDeep, Aesthetic Plast Surg. 2001, 25, 249-255 ). This is used in plastic and reconstructive surgery. Such injections alone serve the volume effect, for example, for the smoothing of wrinkles. Although here (at least to a certain extent) an uncontrolled spread of the injected fluid in the tissue to be suppressed (for example, in the wrinkle smoothing in the eye and lip area), but here are no active substances or body parts, such as magnetic particles, with high concentration and homogeneity and administered with permanent very sharp demarcation against surrounding tissue. The more liquid the gel to be administered, the more practicable is the possibility of injecting it, but the greater is the danger described that it is not defined as intended, locally stable and markedly enriched in the tissue, but in turn spread uncontrollably and with the said disadvantages in the body ,

Gels are also used as delivery systems for the delivery and delivery of drugs. For example, a hydrogel-based carrier system of the University of Illinois (USA) has been known ( JR Tauro, RA Gemeinhart: Matrix metalloprotease triggered delivery of cancer chemotherapeutics from hydrogel matrixes, Bioconjug. Chem. 2005 Sep-Oct; 16, 5, 1133-1139 ), with which the administration of drugs that affect the activity of MMPs (Matrix Metalloprotease), can be controlled. Here, as already described above, again a specially metered release of active substance in the organism are made possible. The undesirable side effects and risks have also been mentioned.

The Administration of magnetic nanoparticles in tumor tissue for the purpose a thermal ablation, for which one said possible high density and homogeneity reaches this particle with sharp demarcation to adjacent tissue is not known in this context.

Also known is the administration of substances directly into the tissue, which solidify after application, for example elastomers (eg. US 4,545,368 ), or which cause a vascular occlusion to suppress the tumor nutrient supply, for example Lipiodol (eg company brochure or internet presence of Guerbet GmbH).

In this method, water-oil emulsions or particulate substances are formed for chemoembolization, these emulsion bubbles or particles due to their size in Fix vessels of the diseased tissue and there release the appropriate ingredients for proper treatment and / or prevent the supply of nutrients through the Gemfäßverschluss (occlusion). In this context, the use of magnetic particles for vascular occlusion has also become known in order to deposit these particles for the per se known hyperthermia and thermal ablation mentioned in the tumor tissue, wherein the closed tissues are to be destroyed by means of magnetically induced heat (for example P. Moroz, C. Metcalf, BN Gray: Histologic analysis of liver tissue following hepatic arterial infusion of ferromagnetic particles in a rabbit tumor model, Biometals ,, 16, 3, 2003, 455-464 ; P. Moroz, SK Jones, C. Metcalf, BN Gray: Hepatic clearance of arterially infused ferromagnetic particles, Int J Hyperthermia, 19, 2003, 23-34 ).

This Procedure, also known as ferromagnetic embolization hyperthermia, is however exclusive applicable to well vascularized tumors as well as to diseases, where the tumor-bearing Vessels too easily accessible are. Furthermore are due to the said occlusion only emulsion blisters and Particles with a certain minimum size (usually from 1 micron diameter) for use suitable. For treatment by hyperthermia and thermoablation (out establish of the compatible Magnetic field and homogeneity the magnetic particle distribution) particularly suitable nanomagnet particles are therefore for such treatment is not provided.

Furthermore there is a risk of occlusion of vessels per se not just the nutrient supply the affected but also other (healthy) tissue is affected. The impact of the occlusion on healthy tissue is otherwise poor controllable. There is still the urgent need, if possible small magnetic particles so accumulate in the tumor tissue that the particles throughout the diseased tissue area with homogeneous particle distribution be deposited without healthy tissue (at least to margins around the tumor) neither by the injection nor by the thermal Harm treatment or to endanger.

A curing or solidification of substances, such as from cooling Gelatin is known, requires time and possibly additional Means that support solidification. Also during this Phase, which can be longer depending on the application, the injected fluid (at least after application and later still in decreasing effect) with the problems already pointed out the endeavor the tumor damaged To drain out tissue and to infiltrate the adjacent healthy tissue. Thus, despite increasing solidification of the injected and the magnetic particles containing liquid the particle distribution in the tumor-damaged tissue at least in the initial phase of solidification until its completion after before run largely uncontrolled. The consequences would still be always firstly no for the treatment result sufficiently sharp-contoured delimitation against healthy tissue and second, the continued inadequate enrichment in terms on particle density and homogeneity. In addition, the solidification / curing phase would be the subsequent thermal treatment by hyperthermia or thermoablation disadvantageous delay, so there is great interest on the part of experts, one application possibility to create, with which by dissipation of magnetic field energy in heat intended tumor treatment possible shortly after deposition of said magnetic particles can and on the basis of a very homogeneous and influenceable selective local particle enrichment a good and predictable Treatment success promises. Furthermore, in the application of Materials, such as gelatin, which must be previously heated to this liquid even the risk of damage in the healthy tissue of the Organism (outside the said border zones of the tumor) can not be excluded.

In the US 5,067,952 A special electromagnetic probe for the controlled administration and propagation of a simple aqueous nanoparticle solution in or on a tumor in the tissue is presented. This probe releases ferromagnetic particles through different pores, not just in one direction but in several directions. However, this still does not solve the aforementioned problems of an uncontrolled "flowing out" of the deposited magnetic particles, an inadequate homogeneity of the particle distribution and the associated insufficiently effective tumor control, as well as the damage and endangerment of healthy tissue.

Furthermore, substances are generally known whose flow velocity / viscosity depends on their motion per se and which, also known under the term of thixothropy, for example in construction (concrete) and in craft (color technology) are widely used (eg. Geraldine Buchenau: "The rheological properties of a self-compacting concrete with stone flours, Fraunhofer IRB Verlag, 2004 ). About applications, especially in the treatment of tumors, such thixothrope substances has not become known in the art.

The invention is based on the object, magnetic particles, with defined density and homogeneity, with influenceable and stable position sharp distinction to the environment and under good handle administration locally in the intended medium, in particular within or directly at the edge of tumor-infected organic tissue, enrich.

For medical Applications should be as possible immediately following heat treatment the magnetic Nanoparticles well injectable, stable, with very distinctive local Demarcation opposite adjacent healthy tissue and with high and predetermined particle density can be introduced into the tissue-diseased area, without that this, upon or after their deposition uncontrolled the situation change. On the one hand, it should in the subsequent thermal treatment of the diseased body tissue a damage healthy tissue (at least to margins around the tumor tissue around). On the other hand should also be guaranteed be that by uncontrolled spread of the magnetic particles in the body not due to deviating particle density and homogeneity in the intended body zone the danger of their being dangerous incorrect or inadequate treatment during subsequent heating arises.

to solution This task is the magnetic particles, which localized in the intended medium are to be introduced, according to the invention in one known fluid carrier substance taken up and mixed, whose flow rate is with their Movement changed (thixotropic fluid). With it changed the viscosity of the magnetic particles containing and applied in the medium Mixture of substances very quickly only by stopping application movement, so that the substance mixture with and after the accumulation in Tissue by rapidly decaying flow rate and thus associated high viscosity essentially no longer spreads unchecked and in the administered situation remains.

The proposed substance mixture from the fluid thixothrope carrier substance and the magnetic particles over any channels, for example tubes, and even about small-caliber lines, such as tubes and cannulas, slightly into the medium because of the pressure with which the mixture of substances is administered, depends on its flow rate / viscosity. So can the substance mixture with appropriate pressure and low viscosity well and workable even through narrowest channels, such as the cannulas, in the intended medium be introduced and sits down with stop motion there immediately with high viscosity for local deposition of the particles. This succeeds in Also need big Amounts of magnetic particles to be enriched with high defined Particle density with good 'handling' controlled deposit, without the introduced deposition mass, as described above, apart and out of the tumor tissue into healthy tissue flows and theirs Situation in the medium changed significantly. On This is due to the high viscosity in the medium that occurs with deposition a stationary one Enrichment with defined and high particle density achieved, wherein the enriched deposition mass to the environment with sharp Contour delimits.

For the said medical applications this means that the magnetic nanoparticles, after their deposition in the medium (tissue of a living organism) by a magnetic field for the purpose of a thermal treatment morbid Heated tissue areas be very practical in the fluid thixothropen carrier with high flow rate and low viscosity over one cannula injected into the tissue and there as a result of the declining Movement changes small flow rate and high viscosity and stable be deposited. The substance mixture does not have to be more controllable Deposit is particularly slow to be injected, and rather is with tolerable Injection times administrable. Also need to follow the heat treatment of the tumor-damaged Tissue no solidification phases of the injected substance mixture awaited or the substance mixture other substances, for example for one independent of the movement additional consolidation or curing, be added.

The Defined controlled deposition of magnetic particles allows for later thermal treatment both an effect of local type (sharp-contoured local Limitation to avoid damage to healthy tissue) also a therapeutic effect by the magnetic particles in the intended high local density and with homogeneous distribution enriched in the diseased tissue to be thermally treated become.

Consequently As a result, this is caused by the substance mixture according to the invention advantageous deposition of the magnetic particles an intended improved Therapeutic treatment with much lower risks described above Kind of achieved the patient.

The Application of the proposed thixothropen substance mixture with the described advantages for the good and practicable introduction of locally into the media to be introduced Magnetic particles as well as for the local selective and defined deposit is not on the limited as described above and by way of example.

• – wenigstens einer Ampulle (Ampulle A), welche die in einer wässrigen Lösung suspendierten magnetischen Nanopartikel enthält,
• – wenigstens einer weiteren Ampulle (Ampulle B) mit der fluiden thixothropen Trägersubstanz, wie Poly-Lactat-Säure, Mannitol, Silikone, Hyaluronsäure, organische biokompatible Hydrogele,
• – ein oder mehreren steril verpackten Spritzen mit Kanüle zur Vermischung der Inhalte der Ampullen A und B,
• – ein oder mehreren Sonden mit Kanüle zur Injektion der Mischung aus den Ampulleninhalten in das Medium,
• – ggf. ein oder mehrere Thermosensoren zur Applikation sowie
• – einer Anleitung zur Verabreichung und ggf. Dosierung

besteht.For administration of the thixothropic substance mixture, an application kit is proposed, which at least

• At least one ampoule (ampoule A) containing the magnetic nanoparticles suspended in an aqueous solution,
• At least one further ampoule (ampoule B) with the fluid thixothropic carrier substance, such as poly-lactate acid, mannitol, silicones, hyaluronic acid, organic biocompatible hydrogels,
• - one or more sterile syringes with cannula for mixing the contents of ampoules A and B,
• One or more probes with cannula for injecting the mixture of ampoule contents into the medium,
• - If necessary, one or more thermal sensors for application as well
• - Instructions for administration and if necessary dosage

consists.

Advantageous is when the application kit several ampoules A with a suspension the magnetic nanoparticles in different average particle size distribution, matched to the parameters of the used magnetic Alternating field, as well as several ampoules B with different thixotropic excipients contains, so that the user for application suitable for this purpose from this Kit can create.

The Invention will be described below with reference to an embodiment for injection of a thixotropic medium in the human body with the aim of a subsequent magneto-thermal heat treatment closer to tumors explained become. Such a medium is injected into diseased tumor tissue, to deposit magnetic nanoparticles there. On the one hand, this should Medium good, fast, with low forces and thus the patient preferably On the other hand, according to the object, the deposition should be injectable with little stress the magnetic nanoparticles in tumor tissue are stable and stable in position with very prominent local Demarcation opposite adjacent healthy tissue and with high and predetermined particle density can be introduced without the magnetic nanoparticles for reasons mentioned above at or uncontrolled change their position after their deposition.

The to be introduced thixotropic medium consists of a mixture of a known thixotropic liquid (poly-lactate acid, mannitol, Silicones, hyaluronic acid, organic biocompatible hydrogels) and magnetic nanoparticles, preferably iron oxides with, for example, up to 20% by weight. The magnetic nanoparticles can for the purpose of suspension and avoiding aggregates with a wrapper Have polysaccharides. In adaptation to the parameters of the alternating magnetic field used for the subsequent magneto-thermal heat treatment can magnetic nanoparticles with different average particle size distribution (if possible narrow particle size distribution, between 1 nm and 10 nm or even larger, but at most 1 μm with the goal of avoiding emboli).

To the unique identification of a tumor and its three-dimensional Location with imaging techniques, the tumor by means of a suitable Probe, consisting of a non-magnetic shell and an inside Needle, punctured and the thixothrope medium slowly infiltrating (eg about 50 μl per minute) into the tumor center, possibly in different three-dimensional positions within or directly in the edge zone of the tumor, injected to make the magnetic nanoparticles homogeneous within and in the tumor border area to deposit. The deposition of the magnetic material in the tumor margin area has to the advantage that in analogy to current operational procedures, a safety margin of healthy tissue around the tumor of some Millimeter thick (usual is in practice a safety margin of about 1 cm) in the treatment with is included. All the more important is a sharp-edged demarcation of the deposited magnetic material to the environment, in order for the greatest possible treatment success preferably little healthy tissue in the magneto-thermal heat treatment to suffer.

The thixothrope medium leaves yourself over a small caliber cannula inject easily, given the pressure with which this is administered is dependent on its flow rate / viscosity. So can the thixotropic medium containing the magnetic nanoparticles advantageous with compatible Injection times and high flow rate and low viscosity good and practical manageable in the intended organic Tissue (for example, the female breast) are introduced. There The thixotropic medium accumulates through the decaying movement (decreasing flow velocity and increasing viscosity) immediately stable off, so for said defined and stable deposit neither special slow and controlled injections will still be needed separate solidification phases are awaited or initiated have to.

It is expedient, immediately after the application of the magnetic material to remove the metallic cannula and by a suitable Thermosensor to be able to monitor the temperature development during the exposure of the tumor-bearing organ.

to Providing the necessary components for the injection offers itself an application kit that caters to different applications will and users the opportunity offers the components themselves according to need and purpose to put together.

One such kit consists of at least a first ampoule (ampoule A), which in an aqueous solution suspended magnetic nanoparticles or ferromagnetic material in powder form of different average particle size distribution, matched to the parameters of the used magnetic Alternating field, contains. At least one more ampoule (ampoule B) contains the thixothrope Medium, such as poly-lactate acid, mannitol, Silicones, hyaluronic acid, organic biocompatible hydrogels.

immediate before the therapeutic application, the contents of ampoule A in ampoule B by means of a sterile syringe and by up and Pulling off in motion and thus kept in the liquid state. The freshly prepared mixture is then by means of a suitable Probe, as described above, introduced into the tumor.

It is advantageous if the application kit suitable sterile syringes with cannula and a probe, consisting of a plastic sheath and an inside lying metallic needle with good contrast in known radiological imaging procedures.

Conceivable is the provision of various kits, containing ampoules Suspensions of magnetic nanoparticles of different average particle size distribution in adaptation to the alternating magnetic field to be used and / or different Magnetic materials as well as different thixotropic liquids contains. Thus, the application-specific suitable for the particular application Application be compiled. In addition, each can according to application requirement different thermosensors (eg selectable Length and Thickness) are provided. Furthermore, a detailed protocol for Procedere as well as a concrete instruction for dosage depending on attached to the tumor diameter to be treated.

Claims (8)

Substance mixture for local deposition of magnetic particles in a medium, in particular for localized deposition of magnetic nanoparticles within or directly on the edge of tumor-contaminated organic tissue, wherein the substance mixture is provided with the magnetic nanoparticles for application for its subsequent magnetic field controlled heating as a tumor treatment, characterized in that the magnetic particles are mixed with a fluid thixothrope carrier substance. Substance mixture according to claim 1, characterized in that that for a medical use of the magnetic particles, in particular to the local Deposition of magnetic nanoparticles in the tissue of a living organism, a biocompatible thixothrope component, for example poly-lactate acid, mannitol, Silicones, hyaluronic acid or organic biocompatible hydrogels, is provided. Substance mixture according to claim 1, characterized in that that as a carrier Poly-lactate acid, Mannitol, fatty acid ethyl ester, Polyethylene glycol is used. Substance mixture according to claim 1, characterized in that that as a carrier a gel-like thixotropic liquid, for example, silicones, hyaluronic acid, organic and biocompatible hydrogels, is used. Use of the substance mixture according to claim 1, characterized in that this in one or more small caliber Pipes, for example tubes, is introduced into the medium. Use of the substance mixture according to claim 1, characterized in that this for medical applications through a probe with cannula injected into the tissue. Use of the substance mixture according to claim 1, characterized in that this under control by ultrasound is introduced into the medium. Application kit for using the substance mixture according to one or more of claims 1 to 7, comprising at least one ampoule (ampoule A) which contains the magnetic nanoparticles suspended in an aqueous solution, - at least one further ampoule (ampoule B) with the fluid thixotropic vehicle, such as poly-lactate acid, mannitol, silicones, hyaluronic acid, organic biocompatible hydrogels, - one or more sterile packaged syringes with cannula for mixing the contents of ampoules A and B, - one or more cannulated cannulae for injection the mixture of ampoule contents in the medium, - if necessary, one or more thermosensors for application and - instructions for administration and possibly dosage.