WO2006134166A2

WO2006134166A2 - Pharmaceutical active ingredient for penetrating the blood-brain barrier combined with an active ingredient obtained from biogenic poisons to combat brain tumours

Info

Publication number: WO2006134166A2
Application number: PCT/EP2006/063281
Authority: WO
Inventors: Dirk Weickmann
Original assignee: Toximed Gmbh
Priority date: 2005-06-15
Filing date: 2006-06-16
Publication date: 2006-12-21
Also published as: DE102005027665A1; WO2006134166A3

Abstract

The invention relates to a pharmaceutically active ingredient and to a method for the production thereof for functionally penetrating the blood brain barrier for treating a brain tumour. Said active ingredient contains a pharmaceutically active amount of the total residual poisonous cocktail which is released by latrotoxine, from the poison of certain types of Latrodectus spiders.

Description

Pharmaceutical agent for overcoming the blood-brain barrier in combination with a drug derived from biogenic toxins against brain tumors.

The composition and functioning of the blood-brain barrier are still only partially understood. This barrier plays a role in the protection of the brain from harmful substances, but also allows a regulated supply of energy.

Our body consists of individual organ systems and organs that require different but constant conditions for their function, for example, of nutrients, hormones or electrolytes. All organs are connected by the blood circulation. Since all components for the supply but also for the purification of the body are contained in the blood, filter systems must ensure that only the required substances are allowed through or partially retained for the individual organ systems.

In this context, among other things, the blood-tissue barrier, also known as blood-parenchyma barrier, the blood-liver barrier, the blood-cerebro-barrier, the blood-brain barrier, the cerebro-cerebral barrier , the blood-nerve barrier, the blood-retinal barrier and the placental barrier. In these filter mechanisms, the passage of certain substances from the bloodstream into the respective organ system is prevented or restricted by a so-called barrier effect if these organ systems do not require the constituents or only in a relatively low concentration.

These "barriers" are not self-contained organs, but are formed from a multitude of cells and intercellular spaces that allow blood gases, nutrients and certain chemicals to pass through, or retain macromolecules as endothelial pores, and can not inhibit passage as lipid membranes in the vessel wall lipid-soluble substances or to exert a selective effect of active transport processes in the capillaries The brain and the nerve tissue are protected by two filter systems, the blood-cerebro-spinal barrier and the blood-brain barrier.

The existence and function of the so-called blood-brain barrier has been known for over 100 years and by Paul Ehrlich in 1885 in the experiment been proven. Within the central nervous system, the spaces between the neurons are almost completely filled by glial cells and their foothills. The entire metabolism of nerve cells passes through these glial or endothelial cells. They are used for the installation of nerve cells and nerve fibers and for their nutrition and isolation. One form of glial cells is the astrocytes. They have numerous processes with which they attach themselves to the wall of the capillaries and form a nearly columnless endothelial lining surrounding the capillaries on all sides. These endothelial cells are linked by "tight junctions" and selective selective permeability, which allows only particles smaller than 20 nm in diameter to pass through, so that all of the neuronal metabolism passes through this endothelial network, which is in the blood Gets substances like a biological filter if necessary, but keeps harmful substances away from the nervous system for brain function This endothelial network and the endothelial cells that line the capillaries as a basal membrane are called the blood-brain barrier Unimpeded transmission of oxygen, carbon dioxide, D- Glucose, D - hexose, some L - amino acids and lipid - soluble substances that are necessary for the supply of the brain, as well as release products into the blood The endproducts of the astrocytes provide a certain barrier for many substances like certain hormones, non - lipid soluble ones , water-soluble and chemical substances as well as proteins, thereby ensuring the maintenance of a constant environment for the neurons of the nervous system.

The cell structure of the astrocytes is arranged so that it forms an effective barrier to higher molecular substances and organisms. It is also not completely dense under normal conditions, so that some particles can always penetrate this barrier. In infections, traumas, inflammations, intoxications, hypoxia, fever and in the area of tumors, the tight junctions between the endothelial cells are distended by the swelling of the astrocytes and are much more permeable to other substances. The change in the width of the glade is due to swelling and swelling of the endothelial cells. The basal membrane of the capillaries is not a closed layer. Depending on the density of the fiber network, pores develop in the membrane, which are actively involved in the mass transfer. Long before the possibility of antibiotic treatment, the permeability of the blood-brain barrier has been increased by artificial fever production similar to the process of infection and exploited for the treatment of central nervous system syphilis and psychiatric shock treatment by bringing drugs directly to the brain Has. After the end of the action of the conditions influencing the blood-brain barrier, the temporary permeability forms again.

Termozolomide (Temodal, registered), a lipophilic alkylans, is currently undergoing clinical research for the chemotherapy of patients with brain tumors of solid tumors. It overcomes the blood-brain barrier and increases the radiosensitivity of tumors in simultaneous radiotherapy.

However, the disadvantages of radiotherapy are known. Currently, tumors, as the most dangerous and dreaded diseases of our time, are being fought in a very radical and less environmentally friendly way. As a simple distinctive

Keywords can apply here:

Steel, beam and chemo

This means that tumors, if reasonably achievable, are in principle cut out with the steel of a knife, burned by a wide range of irradiation, or destroyed by so-called chemotherapy with aggressive cytotoxic agents that attack even healthy cells.

Both with normal scalpel and ionizing treatments

Radiation is a spatial limitation of the surgical area is not possible. It will inevitably destroy healthy body cells. The unwanted

Side effects of chemotherapy are well known.

In contrast, however, it was also trying to make a cancer therapy deserving of its name in a more subtle way. For this purpose, the rich treasure of nature was used.

For this purpose, amongst others, many highly active substances isolated from toxic organisms in therapeutic doses are used as medicaments

The use of these biogenic poisons began in the history of mankind already in the primeval times when they served to kill prey with poisoned weapons. For the safe use of these poisons, however, from the beginning certain basic knowledge about their treatment and effectiveness was required. The further attempts to decode the composition of the chemical structure of biogenic toxins later led to the targeted search for certain active substances as the actual cause of observed effects.

In particular, following the request made by Paracelsus (1493-1541) to isolate the active ingredients of medicinal plants, which contributed to the development of latrochemistry, ie chemistry in terms of its medical scope, these efforts are likely to have intensified. In particular, the art of distilling fabrics has been put to the service of research, providing a variety of essential oils and volatiles. But for the isolation of other agents or even for their chemical breakdown of the then known methods were insufficient. It was not until the beginning of the nineteenth century that the development of technical skills in chemistry had progressed far enough to usher in the era of isolation of pure active ingredients from biological material. First of all, the differences in the solubility of the investigated substances in various solvents were used to separate the desired active substances from the accompanying substances. Here, for example, with precipitation centers, the differences in the distribution behavior between two immiscible liquid phases, in the volatility and in the chemical reactivity were observed,

A tremendous upsurge in separation technology, the way to identify drugs to fight disease, made it possible to develop chromatographic techniques in the mid-20th century. Starting from the distribution between a mobile and a stationary liquid phase, from the adsorption, the molecular sieve effects, the ion exchange, the affinity (in particular of proteins) to certain chemical connections (eg enzyme substrates) and the mobility of charged molecules in the electric field, a multiplicity became developed new separation techniques

Recently, many pharmaceutical agents have been developed from biogenic toxins. Thus, DE 19961 141 A1 discloses a pharmaceutical active substance in which it has been found that constituents of spider venoms from spiders of the family Sicaridae can be used for the treatment of tumor diseases. In this case, a peptide toxin from the venom of this spider species, another antagonistic substance obtained from the venom and / or a combination of these constituents are used medicinally in the main. It can be used for the treatment of tumor diseases as well as parallel or supportive to tumor operations and residual tumor tissue can be destroyed. In the therapy, genetically modified body cells (tumor cells) can be destroyed because the active ingredient recognizes the altered surface structure of such cells and kills without complications .. The total toxicity of this spider, so to speak, a cocktail of different substances, is lethal because of its even in small doses, not pharmaceutically usable.

However, this known active ingredient does not work in vivo in any combination in a facial tumor, in particular not in a particular type of brain tumor, namely an oligodendrocytoma.

In addition, it is necessary for successful therapy that this drug largely overcomes the blood-brain barrier. With conventional means, this only succeeds at about 30% to 40%.

It is therefore the object of the active compound according to the invention, while effectively overcoming the blood-brain barrier, to effect a complication-free killing of cancerous body cells from the area of the brain tissue, especially the rare brain tumor oligodendrocytoma, with an active ingredient obtained from biogenic poisons. In this case, a solvent suitable for this purpose must also be indicated.

This object is achieved by an active ingredient combination according to one of claims 1 to 14, or by a method according to claim 25.

In order to overcome the blood-brain barrier, it is preferable to obtain active substances from the poison of spiders of the "black widow" species Latrodectus. These belong to the genus of spherical spiders (Therididae). Characteristic of this Animals is the big abdomen that reminds of a bullet. The front body is relatively small in proportion. The males reach a length without legs up to 5 mm, the females at least 10 to 18 mm. These animals have a brownish to black lacquer color. Almost always red, orange or yellowish drawings are visible on the hind body. They can be found in a wide variety of areas, and some are also found in the cities. The forest is usually not accepted as a habitat.

The following types are used:

a) Latrodectus bishopi b) Latrodectus curacaviensis c) Latrodectus dahli d) Latrodectus erythromelas e) Latrodectus hasselti f) Latrodectus katipo g) Latrodectus menavodi h) Latrodectus rhodesiensis i) Latrodectus revivensis j) Latrodectus schuchi k) Latrodectus tredecimguttatus

I) Latrodectus variolus m) Latrodectus hesperus (additionally only in children) n) Latrodectus corallinus (additionally only in children)

The Black Widow, as used in homeopathy, occurs mainly in America along the Pacific coast to Canada. The homeopathic poison of the black widow is an important remedy for angina pectoris. This spider usually keeps away from human settlements and lives near the ground between stones and scrub. But where to find a spider are usually still several copies in the immediate vicinity.

Latrodectus bishopi occurs in central and southern Florida. Latrodectus curacaviensis is native to the temperate zones of North and South America, as well as to the Netherlands Antilles. The females are glossy black all over the body, only on the abdomen they have red to orange conspicuous drawings. The legendary terrible poison is dangerous for a human being, but only in very rare cases fatal.

Latrodectus dahli is found in Iran.

Latrodectus erythromelas is found in Sri Lanka.

Latrodectus hasselti is found from India to Australia and New Zealand and is often found in cellars, garages, sheds or outside WC houses. These spiders also like to live under stacks of wood and other building materials or even clutter.

Latrodectus katipo is New Zealand's only poisonous spider. It lives in most coastal areas of New Zealand, except in the extreme south. It is found near the ground in grasses and driftwood. The bite of Katipo can be deadly, but the antidote works within three days.

Latrodectus menavodi is found in Madagascar and the Seychelles.

Latrodectus rhodesiensis is native to southern Africa.

Latrodectus revivensis is native to Israel, especially in the Negev.

Latrodectus schuchi (recently called Latrodectus lilianae) lives in Europe only in Spain, namely in Aragon.

Latrodectus tredezimguttatus is very common in southern Europe in cereal fields, especially in the Mediterranean, partly in Asia and Africa. The appearance of this spider is characterized by 13 red spots on the abdomen in a completely shiny black body. Frequently one finds the irregularly built nets near the soil. There are always newer threads to the net it is very stable. The center of the net forms an inverted shape with the shape of a basket and is usually found under an object such as a stone, a branch or in a wall crack.

Latrodectus variolus is found, for example, in America in Michigan. Female specimens have a red dot on the underside of their abdomen, males do not show it, but they wear yellow and red ribbons on their backs.

The active substance according to the invention is extracted from the total latrotoxin-free

Residual cocktail of the individual spiders obtained, wherein a Peptidtoxin - mixture with a molecular weight of 10 to 80 kDa and biogenic amines with a

Molecular weight of 500 Da to 3000 Da are used.

The Latrodectus poison consists of 6 to 7 different proteins

Molecular weights from 5 kDa to 130 kDa, of which the latrotoxin is a highly potent neurotoxin.

In this case the residual venom cocktail of the Latrodectus species mentioned under a to I) is used.

The latrodectus species mentioned under m) and n) are also found in children up to and including

Age of about 12 years can be used.

The residual poison cocktail thus obtained is transformed into the special one described below

Solvent incorporated to saturation.

Preparation of the solvent for the active ingredient according to the invention.

This solvent is composed of several components. The preparation in 3 processing stages is described below:

1. As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated into 15 ml of 0.9% NaCl solution.

Tarantula D4 is mixed in a homeopathic manner with shaking to the center of the earth with 15 ml of the 0.9% NaCl solution. As is known, in homeopathy the patient does not receive the drug in question in his mother tincture, but in a dilution stage. The founder of Homeopathy, Samuel Christian Hahnemann, made the paradoxical observation that the effect of a drug behaves inversely proportional to the concentration. The more the stock solution is diluted, the more effective it becomes.

The D-dilution steps are prepared by adding 1/10 of the stock solution to 9/10 alcohol and then shaking. This gives the first dilution of Dl of this dilution take again 1/10 and shake it with 9 parts of alcohol, and you get a D2. Thus, this procedure continues until finally high potencies, e.g. D 200 arise. Nevertheless, these are highly effective medicines. However, in order to search for an explanatory model, one has to say goodbye to physics, which works with simple linear substance-related theses.

2. To the solution obtained under 1. add up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca.

Of the kind Loxosceles are in the warmer up to the tropical areas of

North America, Central America, South America and the Caribbean represent about 50 species.

In Africa to the Mediterranean and southern Europe are about 20 species of

To find Loxosceles.

The mostly colored in brown tones animals reach a length of the body (without

Legs) from 8 to 15 millimeters. These spiders are active especially at night and very shy. Your network is irregular. As a shelter, they seek out dark spots under stones or under foliage. Loxosceles laeta is mostly in

Basements, garages, sheds, stables or even to find in the apartments themselves.

It must be assumed that the room temperatures in the buildings made it possible for this species to spread so far, even in colder regions. Loxosceles species bite only in strong physical contact. Especially in the living area, the bites are registered, which have a symptomatology similar to a mosquito bite. There is the concept of "necrotic arachndism". This describes skin necrosis after bites of the Loxosceles species. Necroses are also known after bites from other spiders.

3. Due to differences in the proportions of the total poison cocktails used, it is sometimes necessary to coat the whole poison cocktail in anhydrous formic acid, which in turn is added to 1 to 2 ml of the total extract of Bulldog ants. This amount refers to an amount of the total poison cocktail of 10 ml.

The Bulldog ants are ants belonging to the family of the Myrmicinae.

They live in Australia. There are many types of them and they are the largest

Ants on the earth. They can reach a length of up to 40 millimeters. They are diurnal and come in different sizes and colors.

The Bulldog ants have a long head, big eyes and strong jaws.

They often attack in large numbers and their bite is poisonous. Thirty of these ants can kill a human.

Another type of bulldog - ant is small, black and moves forward jumping. This species creates jumps in a height up to 20 centimeters.

The special pharmaceutical active ingredient is then incorporated into the solvent thus obtained for the specific application in question. In the present case, the active ingredient according to the invention is incorporated to overcome the blood-brain barrier in this solvent to saturation.

Extraction and further processing of bioqenen toxins as part of the solvent described above.

The substances used according to the invention for the pharmaceutical active substance can be obtained in a natural way from spider animals of the genus Loxosceles. These poisons were originally used for prey and Predigestion of animal protein. This natural mode of action can be obtained by a preserving, gentle recovery of the poison base material (eg by manual milking).

In contrast to conventional milking methods of arthropods by means of an electrical method (Weickmann D. (1991): Husbandry and Poisoning of Sicariidae, Arachnologische Anzeiger 16, pp. 12-13, and further Weickmann D., Burda R. (1994): Electrophoresis of Scorpion venoms, Electrophoresis Forum 1994, Abstracts, Technical University of Munich), in which the poison is withdrawn from the animals via an electrical impulse, which causes the contraction of the venom glands in the animals (the animals are preferably undercooled), according to the present Invention of the poison cocktail via a manual process in which the animals are stimulated by the exploitation of their natural defense behavior to deliver their venom received.

According to one embodiment of the invention, a manual milking of the spiders is provided. This real, genuine genuine poisons are obtained, in contrast, for example, in the electric milking, by electron flow restructured substances or molecules are obtained, which may be changed in their mode of action, or substances may be present in the poisons Otherwise the animal would not give up. These substances may, but not necessarily, negatively impact the efficiency of the medically active compound contained in the poison cocktail. By default, an analysis and / or quality control of the crude toxin mixture can be carried out by electrophoretic methods.

For manual milking subadult females of the above families and genera were fixed with the fingers of one hand supine and stimulated by touching the blunt side of a placed on a sterile syringe sterile cannula to the chelicer to deliver the poison .. The room temperature was usually about 21 to 27 degrees, the humidity 50% to 70%. The time of day did not matter.

It was preferred that the stimulation time did not last longer than 90 seconds, otherwise the animal would be exposed to unnecessary stress. After the appearance of the venom drop on the venom claws, this was taken with the syringe raised over the cannula. For each animal a new syringe with new cannula was used. Subsequently, the cannula was closed again with the needle protection cover. The sealed syringe together with wounded poison was then directly spent in a desiccator. This was then stored for at least 12 hours in a freezer at least 14 degrees Celsius. The scolopenders and scorpions were milked as described in the Melanoma patent (Clit. Patents "raum &zeit"). In the case of the syringe with the frozen total venom, the needle protection cover was removed after removal from the freezer. The cannula was dipped in solvent, eg, protein solvent (protein column chromatography solvent: 0.25 M Tris / HCl, pH 6.5 to 7.3, 1.92 M glycine, in distilled, deionized water) and raised to 1 ml. Due to denaturation, no SDS is used in the buffer. This gave poison in solution. Subsequently, the cannula was removed. The individual poison solutions in syringes (5 pieces) thus prepared were collected by dislodging (spraying) in a sterile, clean Teflon vial at room temperature. The sealed teflon vial was then shaken on a vortex without foaming for 30 seconds to give a homogeneous solution. After mixing, the entire solution was passed through a Plexiglas funnel (to avoid contamination) into a standing transparent Plexiglass column having an inner diameter of 1.5 cm, a wall thickness of 2 mm and a height of 50 cm and conical down to 1.5 mm, open, filled with 20 mL gel. (Details: Aca 34; matrx 3% acrylamide 4% agarose; fractionation range (MW): proteins: 20 to 350 kDa; exclusion limit: 750 kDa; bead diameters: 60-140 microns). The poison solution thus introduced passed through the gel, displacing the buffer in the gel. Upon complete penetration of the poison solution into the gel, an additional 165 mL of solvent (0.25M Tris / HCl, pH 6.5 to 7.3, 1.92M glycine) was added to the column. This additional solvent displaces the venom solution therein as it passes through the gel. The first 15 ml running down the column were residual buffers and were discarded. After these 15 ml, 40 fractions of 4 ml each were collected. The separation into 4 ml each was due to the physical and chemical properties of the individual fractions, detected by electrophoresis, preferably SDS - PAGE. As a loading buffer for peptide binding and protein protection, Red Load 1 + 2 (Carl Roth GmbH & Co. Co KG, Karlsruhe: SDS-glycerol, bromophenol blue, phosphate buffer, Roi Load 1 with mercaptoethanol, Roti Load 2 without mercaptoethanol). The individual fractions were collected separately in sterile clean screwable 5 ml teflon vials. The quality control of the individual fractions was carried out by means of electrophoresis.

In order to elucidate the structure of the substances, the individual fractions were analyzed by HPLC-MS-MS and by DAD-UV / - spectrometry (DAD or DADI: Direct Analysis of Daughter Ions, direct analysis of daughter ions). Known substances could not be displayed in higher molecular weight range (from 10,000 Da). However, the skeletal determinations indicate that the substances belong to the polypeptide type with toxic components (= polypeptide toxins) and on the other hand to the phospholipase and hyaluronidase type.

Fractions of the same composition can be collected together. For further processing and storage, the individual fractions were freeze-dried, for example, with the following parameters:

The fraction to be lyophilized was cooled to minus 22 degrees Celsius in an open teflon vial loosely covered with perforated aluminum foil. For safe freezing of the sample, a cooling time of 11 hours was observed. Then a vacuum of 0.200 mbar was applied. After reaching the vacuum, the fraction was heated to plus 4 degrees Celsius and maintained at this temperature for at least 24 hours while maintaining the vacuum. After freeze-drying, the teflon vial was screwed airtight with the lyophilized fraction. The storage time is approx. 6 months at room temperature, approx. 1 year at plus 7 degrees Celsius and approx. 15 years at minus 14 degrees Celsius.

Obtaining the drug for the treatment of brain tumors.

In this case, active substances from the venom of scorpions, namely the species Androctonus bicolor, are preferably used. Androctonus bicolor is a subspecies of the numerous Androctonus species. They are also referred to as so-called Dickschwanzskorpione and are considered the most dangerous scorpions in the Middle East and North Africa. Androctonus bicolor occurs mainly in Morocco, eastern Algeria, the highlands of Tunisia,

Libya, Egypt, Sinai, Israel, Lebanon and Syria.

Scorpions have existed for about 405 million years, since the Devonian

Geological era.

The mostly nachaktive animals prefer as habitat the semi-deserts and the

Deserts. Moist areas are avoided. The hiding places are mainly stones. Scorpions also invade human dwellings. However, one finds them more in the vicinity of human dwellings than in the

Dwelling itself.

One should not underestimate the speed of scorpions, because they are in the

Able to run very fast for a short time. As a rule, scorpions are five to ten

Centimeters tall. Androctonus bicolor reaches a size of about nine inches.

The size of a scorpion says nothing about the danger of his poison.

Scorpions can reach the age of six to eight years. Most species grow very fast and can become sexually mature after six to eight months.

The peptide toxin can be obtained by fractionation methods known per se for the separation of proteins from the scorpion venom raw mixture (scorpion venom cocktail). It is preferred here that the peptide toxin is obtained by a column-chromatic purification method. In this case, all enzymes, biogenic amines, free amino acids and other low molecular weight molecules and / or drugs are removed.

It is also preferred that the peptide toxin is present in such an amount as a pharmaceutically active substance that a tumor cell destructive effect of the active ingredient is achieved.

Furthermore, the required proportions are chosen so that the peptide toxin unfolds no or only a small toxic effect in the patient to be treated. Of course, in this case, the amounts of pharmaceutical active ingredients on the type of tumor to be treated and the physical, and possibly psychological, circumstances of the respective patient to vote. The preliminary tests required for such a vote are to be made by a person skilled in the art on the basis of his technical knowledge and ability.

It is further preferred that the pharmaceutical active ingredient according to the invention contains conventional carriers and excipients, such as antibiotics, antimycotics, antituberculosis, antiparasitic agents, cytostatic agents, amino acids, enzymes promoting wound healing and / or mitotic inhibitors. Penicillin / streptomycin, polymyxin / gentamycin (5%), mitopodocide, Vinca rosea alkaloids, bromelaina or bromelains are preferred here.

It is also possible to produce the described active ingredient chemically-synthetically or by genetic engineering methods in recombined form. As is usual with chemical substances, the present invention also encompasses derivatives and salts of the substances provided according to the invention. For example, the peptide toxin may contain one or more, substitutions and / or deletions of

Amino acids include, of course, it must be ensured that the inventive medical effect is maintained.

The recovery of the described active ingredient is carried out in the chemical

Process engineering usual methods.

In lengthy and exhaustive experiments, it has surprisingly been found that certain toxins in the active compound according to the invention have particular lysing effects and that according to their molecular weights.

These are the molecular weights with the values:

18, 21, 23, 31, 42, 48, 50, 63, 79 and 107 (the unit in question is in each case measured in kDa, corresponding to Kilo-Dalton)

Claims

claims

Claim 1:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail of poison from spiders of the species Latrodectus bishopi. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 2:

A pharmaceutical active ingredient for overcoming the blood-brain barrier for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-liberated total residual cocktail from the venom of spiders of the species Latrodectus curacaviensis, b) a peptide-toxin mixture molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated in a solvent prepared in the following manner: d) As the basic ingredient, in FIG ml of 0.9% NaCl solution 7 ml of the homeopathic substance Tarantula D4 incorporated e) To the basic component is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the required proportions of the Total venom cocktail ground in anhydrous formic acid, which in turn is added to 1 to 2 ml of the total extract of ants Bulldog ants, said amount refers to an amount of the total venom cocktail of 10 ml, and wherein the drug for the treatment of tumors in the brain area in a pharmaceutically effective amount comprises the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, wherein all low molecular weight molecules and / or active substances have been removed by purification processes, and wherein h) the molecular weight of the active substance is 18 kDa , Claim 3:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail from the venom of spiders of the species Latrodectus dahli. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 4:

Pharmaceutical active ingredient for the purpose of functionally overcoming the blood-brain barrier for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail from the venom of spiders of the species Latrodectus erythromelas. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 5:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-free total residual cocktail from the venom of spiders of the species Latrodectus hasselti. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 6:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-free total residual cocktail of poison from spiders of the species Latrodectus katipo. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 7

A pharmaceutical active ingredient for overcoming the blood-brain barrier for the purpose of further treating a brain tumor containing in a pharmaceutically effective amount: a) the latrotoxin-liberated total - residual venom cocktail from the venom of spiders of the species Latrodectus menavodi b) a Peptidtoxinmischung with molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated in a solvent prepared in the following manner: d) As the basic ingredient, in FIG ml of 0.9% NaCl solution 7 ml of the homeopathic substance Tarantula D4 incorporated e) To the basic component is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the required proportions, the total drenched in anhydrous formic acid, which in turn is admixed with 1 to 2 ml of the total extract of ants Bulldog ants, this amount being based on an amount of the total venom cocktail of 10 ml, and wherein the active substance is used to treat tumors in the brain area pharmaceutically effective amount comprises the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, wherein all low molecular weight molecules and / or active substances have been removed by purification processes, and wherein h) the molecular weight of the active substance is 18 kDa , Claim 8;

Pharmaceutical active ingredient for the purpose of functionally overcoming the blood-brain barrier for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail of poison from spiders of the species Latrodectus rhodesiensis. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 9:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail of poison from spiders of the species Latrodectus revivensis. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 10:

Pharmaceutical active ingredient for the functional overcoming of the blood-brain barrier for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail of poison from spiders of the species Latrodectus schuchi. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 11:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-free total residual cocktail of toxins from spiders of the species Latrodectus tredecimguttatus. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 12:

A pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail from the venom of spiders of the species Latrodectus variolus. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 13;

A pharmaceutical agent for functionally overcoming the blood-brain barrier for the further treatment of a brain tumor only in children up to 12 years of age containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail of venom from spiders of the species Latrodectus hesperus. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 14;

A pharmaceutical agent for functionally overcoming the blood-brain barrier for the further treatment of a brain tumor only in children up to 12 years of age containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail of venom from spiders of the species Latrodectus corallinus. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the whole poison cocktail is ground in anhydrous formic acid, which in turn is mixed with 1 to 2 ml of the total extract of ants Bulldog ants Amount of the total poison cocktail of 10 ml, and wherein the active ingredient for the treatment of tumors in the brain h comprises, in a pharmaceutically effective amount, the following components: g) a total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor, whereby all low molecular weight molecules and / or active substances have been removed by purification processes, and h) the molecular weight of the active substance 18 kDa. Claim 15:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination from the venom of scorpions of the genus Androctonus bicolor is 21 kDa.

Claim 16:

Pharmaceutical active ingredient for the functional overcoming of the blood-brain barrier for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 23 kDa.

Claim 17:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the further treatment of a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 31 kDa.

Claim 18:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 42 kDa. Claim 19:

Pharmaceutical agent for the functional opening of the blood-brain barrier for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 48 kDa.

Claim 20:

Pharmaceutical active ingredient for functionally overcoming the blood-brain barrier for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 48 kDa.

Claim 21;

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 50 kDa.

Claim 22:

Pharmaceutical active ingredient for overcoming the blood-brain barrier functionally for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 63 kDa. Claim 23:

Pharmaceutical active ingredient for overcoming the blood-brain barrier for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 79 kDa.

Claim 24:

Pharmaceutical active ingredient for the functional overcoming of the blood-brain barrier for the purpose of further treating a brain tumor, according to one of claims 1 to 14, characterized in that the total peptide-toxin combination of the poison of scorpions of the genus Androctonus bicolor is 107 kDa.

Claim 25:

A process for the preparation of a pharmaceutical agent for overcoming the blood-brain barrier functionally for the further treatment of a brain tumor containing, in a pharmaceutically effective amount: a) the latrotoxin-removed total residual cocktail from the venom of spiders of the species Latrodectus bishopi. wherein b) a peptide-toxin mixture having the molecular weight of 10 kDa to 80 kDa, and c) biogenic amines having a molecular weight of 500 Da to 3000 Da are used, and wherein this active ingredient is incorporated into a solvent prepared in the following manner: d ) As a basic ingredient, 7 ml of the homeopathic substance Tarantula D4 are incorporated in 15 ml of 0.9% NaCl solution. E) To the basic ingredient is added up to 0.5 ml of a saturated solution of the total poison cocktail of spiders of the species Loxosceles laeta, or Loxosceles gaucho, or Loxosceles Mallorca, or Loxosceles Menorca, f) Depending on the proportions required, the total cocktail of poisons is ground in anhydrous formic acid, which in turn is added to 1 to 2 ml of the total extract of ants Bulldog ants, this amount being based on an amount of the total poison cocktail of 10 ml, and the active ingredient for the treatment of tumors in the brain area in a pharmaceutically effective amount, the following components: g) a total peptide toxin combination of the poison of scorpions of the genus Androctonus bicolor, wherein all low molecular weight molecules and / or active substances have been removed by purification processes, and wherein h ) the molecular weight of the drug is 18 kDa.

Claim 26;

A method according to claim 25, characterized in that total residual cocktail is alternatively used by spiders of one of the following types: a) Latrodectus curacaviensis b) Latrodectus dahli c) Latrodectus erythromelas d) Latrodectus hasselti e) Latrodectus katipo f) Latrodectus menavodi g) Latrodectus rhodesiensis h) Latrodectus revivensis i) Latrodectus schuchi j) Latrodectus tredecimguttatus k) Latrodectus variolus

I) Latrodectus hesperus (additionally only in children) m) Latrodectus corallinus (additionally only in children) Claim 27:

Method according to one of claims 25 to 26, characterized in that the molecular weight of the total peptide - toxin combination of the poison of scorpions of the genus Androctonus bicolor alternatively a) 21 kDa b) 23 kDa c) 31 kDa d) 42 kDa e) 48 kDa f) 5OkDa g) 63 kDa h) 79 kDa, or i) 107 kDa.