System for administering an active ingredient

Abstract

A system (1) for administering an active ingredient, comprising a magnetizable core (2), wherein the core (2) has a sheath (3) of silicon dioxide, characterized in that the sheath (3) completely surrounds the core (2), wherein the core (2) with sheath (3) has a diameter (D2) of 10 nm to 400 nm, preferably 20 nm to 250 nm, more preferably 100 nm to 200 nm, wherein a coating (4) has been applied to the sheath (3).

Description

[0001] Drug delivery system

[0002] The present invention relates to a system for administering an active ingredient. Furthermore, the invention relates to a method for producing a system for administering an active ingredient.

[0003] BACKGROUND OF THE INVENTION

[0004] While the local administration of drugs to the surface of the body is relatively simple, the targeted delivery of drugs to a specific location within the body remains challenging. The most common approach remains systemic delivery through the distribution of a drug via the blood. Through circulation in the blood, the drug is distributed throughout the body.

[0005] For more targeted drug delivery, magnetizable nanoparticles coated with a drug substance are now also being injected. For example, US Pat. No. 9,393,396 B2 discloses a method and composition of coated nanoparticles for the local hyperthermic treatment of tumor cells. The nanoparticles enriched with a drug substance are guided to a defined anatomical site in the body using a magnetic field, where the nanoparticles can release the drug substance.

[0006] US Pat. No. 7,309,316 B1 describes superparamagnetic nanoparticles with a receptor for specific body cells that are introduced into a selected tissue collection using a biopsy needle. A magnetizable or magnetic rod is inserted through the cannula of the biopsy needle into the area of ​​action of the nanoparticles and positioned there for a predefined time. The nanoparticles attach to the cells for a defined treatment period. After the treatment period, the nanoparticles with attached cells can be removed in a controlled manner using the magnetized or magnetic rod for further analysis due to the magnetic effect.

[0007] US 10,449,160 B2 describes intravenously administered magnetizable nanoparticles that (randomly) accumulate in the newly formed (neoangiogenic) blood vessels surrounding tumor tissue without external intervention and, with their (random) spatial distribution, enclose the tumor. The magnetizable nanoparticles can be coated with an active ingredient, but do not necessarily have to be. EP 2 920 298 B1 discloses silica-coated nanoparticles.

[0008] BRIEF DESCRIPTION OF THE INVENTION

[0009] State-of-the-art systems for the precise delivery of active ingredients still prove inadequate in terms of treatment efficiency and effectiveness. This is due, among other things, to the fact that the particles cannot be positioned precisely enough within the body and, furthermore, do not release the active ingredient in a sufficiently targeted manner. The object of the present invention is therefore to provide a system for administering an active ingredient within the body that can be positioned more precisely and releases the active ingredient more efficiently at the desired location.

[0010] This object is achieved by a system for administering an active ingredient, comprising a magnetizable core, wherein the core has a sheath made of silicon dioxide, characterized in that the sheath completely encloses the core, wherein the core with sheath has a diameter of 10 nm to 400 nm, preferably 20 nm to 250 nm, particularly preferably 100 nm to 200 nm, wherein a coating is applied to the sheath.

[0011] The inventors discovered that, on the one hand, the diameter of the core and the coating are crucial for precisely positioning the system in a patient's body using a magnet. On the other hand, the coating is crucial for the system, as it has the task of absorbing the pharmaceutically active ingredient in sufficient concentration. Therefore, the coating is designed to absorb a pharmaceutically active ingredient or it contains a pharmaceutically active ingredient.

[0012] The diameter of the core and cladding is in the range of 10 nm to 400 nm, preferably 20 nm to 250 nm, and particularly preferably 100 nm to 200 nm. Systems with diameters of 10 to 30 nm have been used successfully in animal experiments. However, since a particle size of 10 nm may be considered problematic for the human organism, sizes of 100 nm to 200 nm are preferred for use in human medicine and smaller sizes in veterinary medicine. The diameter range of 100 nm to 200 nm also represents an optimal ratio between the surface area of ​​the cladding for the coating and the positionability of the system using a localized magnetic field.

[0013] Especially for human medical applications, a core-to-cladding diameter of at least 100 nm is advantageous, since particles with diameters below 100 nm are often excreted by the human body with considerable delay. Particles smaller than 10 nm have been shown to be cell-permeable and could therefore penetrate cells, which is something the invention aims to prevent.

[0014] For compatibility within the body, a complete coating of the core with the silicon dioxide coating is also crucial. This ensures that the core does not come into contact with body fluids or endogenous fluids.

[0015] The magnetizable core is preferably superparamagnetic or ferritic. Superparamagnetic cores have the additional advantage over ferritic cores that they do not form agglomerated aggregates and remain isolated, so superparamagnetic cores are preferred.

[0016] In one embodiment, the magnetizable core is selected from the group consisting of maghemite (y-Fe2O3), cobalt ferrite (CoFe2O4) or mixtures thereof.

[0017] The silicon dioxide coating preferably has pores, as this allows the coating to adhere better to the coating. In this design variant, the coating preferably extends into the pores. The depth of the pores should not exceed 95% of the coating thickness, so that the core is inaccessible to body fluids.

[0018] The interaction of the three parameters core / shell / coating is crucial for whether and for how long the active ingredient can be retained in the system and how it is released at the desired location. As already explained above, it has been shown that smaller or larger cores with the shell and coating do not work, just like other shells or coatings with the correct core size. The coating is important for the storage of a pharmaceutically active ingredient. The coating should therefore be designed in such a way that an active ingredient can be stored in the coating, that an active ingredient is stored there, or that the coating itself takes over the function of the active ingredient. At the same time, the storage of the active ingredient should only be strong enough that the active ingredient is released again at a desired location in the body (and does not remain in the system). The bond strength between the active ingredient and the coating should therefore be balanced.Saccharide-based coatings, i.e., monosaccharides, oligosaccharides, or polymers with saccharide units, have been shown to be suitable coatings. While monosaccharides and oligosaccharides usually dissolve completely upon release of the active ingredient, leaving only the core and coating, polymers can, in some cases, adhere to the coating and release only the active ingredient into the environment. The coating thickness depends on the amount of drug to be administered and the active ingredient itself, but should not be less than 5% of the total radius of the system.

[0019] The diameter of the core is preferably at least 50% and preferably at most 95% of the diameter of the core with the sheath. Particularly preferably, the diameter of the core is 75% to 85% of the diameter of the core with the sheath.

[0020] Regarding the coating, various types of saccharides and polymers with saccharide units are conceivable. Various compounds, such as monosaccharides and oligosaccharides, can be considered. Examples of monosaccharides include hexoses, such as gulose, idose, galactose, talose, allose, altrose, glucose, or mannose, with glucose and mannose being preferred. Oligosaccharides such as sucrose, etc., are also possible.

[0021] Polymers with saccharide units are also suitable coatings, although the active ingredient is usually incorporated into the polymer. Polymers with saccharide units are understood to be polymers composed of monomers, where at least one monomer is a saccharide. For the purposes of the invention, polymers with saccharide units are in particular polysaccharides such as preferably homoglycans (e.g., dextran, glycogen, starch (amylose and amylopectin), pectins, chitin, callose, cellulose, etc.) or preferably heteroglycans (e.g., hyaluronic acid, agarose, alginate, xanthan, etc.), with hyaluronic acid in particular showing good compatibility. The coating can comprise an active ingredient. This active ingredient can be incorporated into the coating or be the coating itself. However, an active ingredient is preferably only incorporated into the coating shortly before application.

[0022] Typical active ingredients include those for cancer therapy, so the active ingredient can be selected from the group consisting of cytostatics, hormones, antibodies, cytokines, signal transduction inhibitors, and protease inhibitors. However, the system can also be used in pain therapy, so the active ingredient can be an analgesic, for example. Furthermore, the system's application is not limited to human treatment but also possible in veterinary medicine.

[0023] The invention therefore also relates to such a system for use as a medicament, e.g. in pain therapy, oncology, veterinary medicine, etc.

[0024] The invention also relates to a medicament comprising such a system and an active ingredient. This may be a medicament used, for example, in pain therapy, oncology, veterinary medicine, etc.

[0025] In one aspect of the invention, a method for positioning systems of the above-mentioned type is also provided, which comprises a rod having a magnetic field, wherein the rod is positioned on the outside of a body on the skin.

[0026] The invention also relates to a method for producing a system for administering an active ingredient. The method comprises the steps: a) providing magnetizable cores; b) coating the cores with a silicon dioxide coating, for example, using a sol-gel process, until the thickness of the cores with coating is between 10 nm and 400 nm, preferably between 20 nm and 250 nm, particularly preferably between 100 nm and 200 nm; c) coating the coating with a coating suitable for absorbing a pharmaceutically active ingredient or which represents an active ingredient.

[0027] If necessary, the active ingredient can be incorporated into the coating immediately or later. Magnetizable particles are used as cores, which can be constructed as defined above. The diameter of the cores is selected depending on the desired thickness of the core and sheath. The cores are preferably selected so that, depending on the desired diameter of the core and sheath, the cores account for at least 50% of this diameter. Corresponding advantageous diameters have already been defined above.

[0028] The coating may comprise first impregnating the coated core with an aqueous solution of a saccharide or a polymer containing saccharide units and then drying to remove water.

[0029] Coating the sheath may also involve first impregnating the coated core with an active ingredient solution and then drying it to remove water.

[0030] The active ingredient is preferably applied as an aqueous solution. It is possible to apply the active ingredient together with the coating, or it can be subsequently incorporated into the coating (e.g., by spraying a dissolved or suspended active ingredient followed by drying the solvent or suspending agent).

[0031] If the coating is the active ingredient itself, analogous techniques can be used.

[0032] DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention is a special method for the minimally invasive, highly localized and personalized treatment of tumors or other lesions inside the body using suitable active substances while simultaneously protecting adjacent healthy tissue areas to the maximum and causing minimal side effects.

[0034] The treatment method in question is essentially based on two components:

[0035] Component A (the system) consists of magnetizable, biocompatible nanoparticles with a superparamagnetic (or ferritic) core, for example, maghemite (γ-Fe2O3) or cobalt ferrite (CoFe2O4), coated in porous silica. The pores of the silicon dioxide coating can accommodate a saccharide solution, such as a glucose solution, or a solution of a polymer with saccharide units, such as a hyaluronic acid solution, as a coating. The adsorbed solution (coating) contains, for example, at least one pharmaceutically active agent for tumor treatment. Alternatively, the coating itself can be the active agent.

[0036] Component B is represented by at least one magnetizable or magnetic object, preferably a rod-shaped permanent magnet or electromagnet. The characteristic dimensions of this object depend essentially on the extent of the lesion to be treated. The geometry and positioning of the at least one object are influenced by the selected (surgical) application technique. The efficiency of the treatment method is increased when the magnetizable or magnetic object moves in an oscillating manner in the vicinity of the area to be treated.

[0037] While the system (component A) is typically injected intra-arterially, a magnetizable or magnetic object (component B) is placed, e.g., by insertion via a trocar near the desired location where the system is to be positioned. However, the system according to the invention can also be positioned using a magnetizable or magnetic object in the form of a rod that has a magnetic field, by positioning the rod on the outside of a body against the skin at the desired location.

[0038] The invention is particularly suitable for a novel tumor treatment and preferably provides for the simultaneous and very precise application of the two components in the vicinity of the tissue to be treated (component A is applied intracorporeally, component B is applied intracorporeally or on the body surface) from two different positions. The time interval between the application of the two components can also be a defined duration, optimizing the drug delivery or effect of the pharmaceutically active agent on the lesion.

[0039] The magnetizable cores with a coating and medication (component A) are introduced into the vicinity of the tumor via the bloodstream (intra-arterial application via syringe or via the arteries via catheter) and release the active ingredient into the surrounding tissue in a controlled manner over a defined period of time. The magnetizable or magnetic object (component B) is positioned near the lesion to be treated, for example, using a (magnetic) biopsy needle, trocar, or catheter. The applied object (component B) remains in the body for a defined period of time (at least several seconds) and can be removed again using minimally invasive techniques.

[0040] Due to the magnetic effect between the introduced magnetized or magnetic object (component B) and the magnetizable cores, the systems (component A) remain in close proximity to the cells to be treated (e.g., malignant cells in the case of a tumor), where they can achieve maximum effectiveness. The drug delivery is facilitated by the movement of the introduced object; this movement can be enforced externally via the biopsy needle, the trocar, a catheter, or by other means of applying component B to the body surface.

[0041] The system is not distributed over a wide area of ​​the body, ensuring maximum protection of healthy body regions. Due to the highly localized effect of this tumor treatment, it can be simplified as "chemotherapy without side effects."

[0042] If the characteristic dimensions of the core and shell are in the range of 100 to 200 nm, they are not cell-permeable and are protected from chemical attacks by the body's own substances by the hydrophilic silica shell; they are biocompatible.

[0043] After the treatment period, the magnetizable nuclei with their coating can be collected again using a magnetic device (e.g., a catheter with a magnetic tip) and gently removed from the body (without leaving any residue). However, those with their coating that are not removed using a magnetic device are also automatically excreted after a certain period of time. Excretion usually occurs via the reticulohistiocytic system.

[0044] Further details and advantages of the invention are set out in the accompanying figures and in the following description of the figures.

[0045] Fig. 1 shows a schematic representation of a system according to the invention.

[0046] Fig. 2 shows the schematic application of the system for treatment in the body. Fig. 1 shows a rough schematic of a system 1 according to the invention with radius r. The system 1 for administering a drug comprises a magnetizable core 2, which is either superparamagnetic (in the examples examined it consists of maghemite (γ-Fe2O3)) or ferritic (in the examples examined it consists of cobalt ferrite (CoFe2O4)). The superparamagnetic or ferritic core 2 has a diameter D1 and is completely surrounded by a sheath 3 made of silicon dioxide. Core 2 together with sheath 3 have a diameter D2. The sheath 3 is porous and has pores, which are simplified as triangular indentations. The depth of the pores should not be less than 95% of the thickness b of the sheath 3, so that a residual thickness a of 5% remains.

[0047] The sheath 3 completely encloses the core 2. The coating 4 is located on the sheath 3, which in the illustrated embodiment comprises a saccharide or a polymer with saccharide units. The saccharide can be, for example, glucose, which was applied to the sheath 3 using an aqueous glucose solution. Polymers such as hyaluronic acid have also been successfully investigated in a similar way. The coating 4 also has an active ingredient, which was applied simultaneously with the saccharide solution or the polymer solution. Cytostatics, hormones, antibodies, cytokines, signal transduction inhibitors, protease inhibitors, and analgesics have been investigated as active ingredients. It is also conceivable for the coating 4 itself to be an active ingredient.

[0048] In oncological studies, cytostatic drugs were used as active ingredients, which - as shown in Fig. 2 - were injected into the blood vessel 10 using the system 1 via a syringe 11, a trocar, a biosie needle, or a catheter. The individual systems 1 are distributed within the blood vessel 10 and are guided and held near a tumor 12 by means of a magnetic field from a magnetic source 14, where they can deliver the active ingredient to the tumor 12 in a targeted manner and exert their cytostatic effect there.

[0049] A system 1 according to the invention was successfully used in a study on rabbits with tumors. The system 1 investigated had a core 2 made of cobalt ferrite and a coating made of silicon dioxide. The diameter D2 of core 2 with coating 3 made of silicon dioxide was 12 to 30 nm, and the diameter D1 of the core was approximately 80% of the diameter D2. The coating 4 was made of hyaluronic acid in one case and glucose in the other, and the layer thickness of the coating 4 was approximately 3 to 4 nm. A cytostatic drug (daunorubicin) was incorporated into the coating 4 as an active ingredient using a spray technique. System 1 was administered with and without the active ingredient (control group 1) by intra-arterial injection via the femoral artery. A single injection of approximately 100,000 systems in 500 μl was carried out. At the time of injection, an external magnetic field was already present in the tumor area.With a single administration, a regression of tumor volume of 70% to 90% was observed within 14 days in the patient group, while no measurable regression of tumor volume was observed in the control group 1.

[0050] In control group 2, System 1 was injected with the drug, but no external magnetic field was applied. In control group 2, a tumor volume regression of 5% to 10% was observed. No significant differences were observed between coating 4 made of hyaluronic acid and that made of glucose, although drug release may be slower with coating 4 made of hyaluronic acid.

Claims

REQUIREMENTS 1. System (1) for administering an active substance, comprising a magnetizable core (2), wherein the core (2) has a casing (3) made of silicon dioxide, characterized in that the casing (3) completely encloses the core (2), wherein the core (2) with casing (3) has a diameter (D2) of 10 nm to 400 nm, preferably 20 nm to 250 nm, particularly preferably 100 nm to 200 nm, wherein a coating (4) is applied to the casing (3).

2. System according to claim 1, characterized in that the coating (4) comprises a saccharide or a polymer with saccharide units.

3. System according to claim 1 or claim 2, characterized in that the magnetizable core (2) is superparamagnetic or ferritic.

4. System according to one of claims 1 to 3, characterized in that the casing (3) made of silicon dioxide has pores, wherein the coating (4) projects into the pores.

5. System according to one of claims 1 to 5, characterized in that the diameter (D1) of the core (2) is at least 50%, preferably 75% to 85%, relative to the diameter (D2) of the core (2) with casing (3).

6. System according to one of claims 2 to 5, characterized in that the coating (4) comprises a saccharide, wherein the saccharide is preferably selected from the group consisting of gulose, idose, galactose, talose, allose, altrose, glucose and mixtures thereof.

7. System according to one of claims 2 to 6, characterized in that the coating (4) comprises a polymer with saccharide units, wherein the polymer is preferably selected from the group consisting of hyaluronic acid, dextran, glycogen, amylose, amylopectin, pectins, chitin, callose, cellulose and mixtures thereof.

8. System according to one of claims 1 to 7, characterized in that the coating (4) comprises an active ingredient.

9. System according to claim 8, characterized in that the active ingredient is selected from at least one of the group consisting of cytostatic agent, hormone, antibody, cytokine, signal transduction inhibitor, protease inhibitor, analgesic.

10. System according to any one of claims 1 to 9, for use as a medicinal product.

11. System for use according to claim 10 for use in human medicine or veterinary medicine, in particular in pain therapy, oncology, hematology and / or immunology.

12. Drug comprising a system according to any one of claims 1 to 9 and an active ingredient.

13. Method for positioning a system according to one of claims 1 to 12, characterized in that a magnetic object, preferably a rod-shaped magnetic object, is positioned on the outside of a body on the skin.

14. Method for producing a system (1) for administering an active ingredient, in particular according to any one of claims 1 to 12, comprising the steps of: a) providing magnetizable cores (2); b) coating the cores (2) with a coating (3) of silicon dioxide, preferably by means of a sol-gel process, until the thickness of the cores with coating (3) is between 10 nm and 400 nm, preferably between 20 nm and 250 nm, particularly preferably between 100 nm and 200 nm; c) coating the coating (3) with a coating (4) which is suitable for receiving an active ingredient or which constitutes an active ingredient.

15. Method according to claim 14, characterized in that the coating (2) of the casing (3) first comprises impregnating the encased core (2) with an aqueous solution of a saccharide or a polymer with saccharide units and subsequent drying to remove water.

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